KR20250138805A - Treatment of mental disorders - Google Patents

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of mental or neurological disorders in mothers of children aged 18 months or younger, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous, intramuscular or subcutaneous route.

Description

Treatment of mental disorders

The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating mothers, particularly lactating mothers, diagnosed with mental or neurological disorders.

Mental disorders can be treated with 5-MeO-DMT or its pharmaceutically acceptable salts. Treatment also improves maternal function.

Moreover, the present invention enables the treatment of mental or neurological disorders in lactating mothers without substantial interruption of breastfeeding.

Mental or neurological disorders in breastfeeding mothers can have a wide range of negative consequences for the affected mother, her infant(s), and her family. For example, women with mental or neurological disorders may develop thoughts of self-harm or harm to their children, and are at increased risk for suicide.

Mental or neurological disorders can further disrupt mother-child interactions, as exemplified by higher rates of disconnected behavior and lower rates of visual and verbal communication between mothers and children. Evidence also suggests a link between maternal mental or neurological disorders and child development, as evidenced by the fact that children of mothers with mental or neurological disorders are at greater risk for impaired cognitive development.

Despite these challenges, treatment options are somewhat limited. Most commonly, known treatments for mental or neurological disorders are associated with limited success, especially in patients with only mild symptoms.

A complicating factor is that for many medications, nursing women are advised to discontinue breastfeeding while taking the medication and for a period of time afterwards, as medications can pass into breast milk and put the nursing infant at risk.

Moreover, research has shown that breastfeeding mothers may be reluctant to start medication due to various concerns.

Consequently, breastfeeding patients with mental or neurological disorders may be faced with the decision of whether to discontinue breastfeeding or discontinue/abstain from therapy.

Against this backdrop, there is a need for improved treatments for mental and neurological disorders, particularly those that effectively address the symptoms of the disorder, induce rapid clinical responses, and avoid disruption to the patient's daily activities, particularly when caring for their infant(s). Treatments should also improve maternal function. Furthermore, there is a need for treatments for mental and neurological disorders that do not require the actual discontinuation of breastfeeding.

Although there has been significant recent interest in hallucinogens for the treatment of mental disorders, these substances have not yet been used in the treatment of lactating women. This is due not only to the general lack of relevant clinical data that would allow for conclusions about the clinical utility of hallucinogens, but also to specific concerns about the potential inappropriate use of hallucinogens in lactating women.

Hallucinogens, including psychedelics, are chemical compounds, some naturally occurring and some synthetic, that are defined by their ability to induce sensory disturbances in humans after ingestion, such as changes in auditory and visual perception, as well as mood and cognitive distortions. The term hallucinogen encompasses a rather broad group of psychoactive molecules with different modes of action. Some mental disorders have been proposed to be treatable, in principle, with psychoactive molecules such as hallucinogens.

However, no psychedelic drugs have been approved by any regulatory agency. In fact, clinical experience with these molecules remains somewhat limited.

One compound already investigated in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020/169850 reports on trials in healthy volunteers and in patients with treatment-resistant depression (TRD), a form of major depressive disorder. Patients with PPD were not included in the trial.

Against this background, it is an object of the present invention to provide a regimen that is more effective than previously described regimens, i.e., a) a greater percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a more rapid onset of clinical response, and/or d) a more durable clinical response.

Another object of the present invention is to provide improved psychotropic therapies and compounds for dosing regimens for such therapies, which have a superior safety profile and/or better tolerability than previously described therapies. Another object of the present invention is to provide improved psychotropic therapies and compounds for dosing regimens for such therapies, which are more convenient than previously described therapies. Another object of the present invention is to provide improved psychotropic therapies and compounds for dosing regimens for such therapies, which are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. Another object of the present invention is to identify specific disease states and specific subgroups of disease states that would benefit from such improved psychotropic therapies.

Another object of the present invention is to improve maternal function in patients suffering from mental or nervous disorders, particularly in nursing mothers diagnosed with mental disorders.

The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a mother diagnosed with a mental or neurological disorder, particularly a nursing mother diagnosed with such a disorder. The disorder is particularly characterized by a depressive episode, such as Major Depressive Disorder (MDD), Persistent Depressive Disorder, Seasonal Affective Disorder, and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Anxiety Disorders, such as Separation Anxiety Disorder, Agoraphobia, Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobias, and Drug/Medicine-Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive-compulsive and related disorders, such as Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain disorders, such as chronic pain, fibromyalgia, and migraines; Mental and behavioral disorders due to psychoactive substance use, such as Substance Use Disorder (SUD); Psychotic disorders, such as schizophrenia; Eating disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality disorders, such as Schizotypal and Borderline Personality Disorder; Autism Spectrum Disorder; Chronic Fatigue Syndrome; and Mental or Neurological disorders associated with HIV, post-COVID conditions, or traumatic brain injury.

In one aspect, the patient may suffer from sleep disturbances.

This treatment enables improvement of maternal function.

Patients to be treated are especially lactating women.

The present invention also allows for the treatment of lactating women without substantial interruption of breastfeeding.

The present invention also provides dosage ranges and dosing regimens useful for the treatment indicated above.

In the context of the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous administration.

5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in a dose or dosage regimen that produces the optimal hallucinogenic experience for the patient. A dose of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt thereof may be administered.

definition

As used in the context of the present invention, unless otherwise stated, the term '5-MeO-DMT' refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic, benzoic, citric, fumaric, hydrobromic, hydrochloric, hydrofluoric, hydroiodic, oxalic, succinic, and triflic acids. A preferred example is the hydrobromic salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming that equimolar amounts are used.

As used in the context of the present invention, a 'patient' to be treated is a mother of a child, typically 18 months or younger, particularly 12 months or younger, who has been diagnosed with a mental or neurological disorder by a licensed professional in accordance with accepted medical practice.

Diagnosis of a mental or neurological disorder may be made, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will be apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or groups of patients who would particularly benefit from the treatment of the present invention. In any case, a diagnosis will be made by a physician or psychologist. It is not sufficient for a human subject to believe that he or she suffers from a disorder.

As used in the context of the present invention, unless otherwise stated, the terms 'treating' and 'treatment' include the management and care of a patient for the purpose of combating a disease, condition or disorder, and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms of the disease or to eliminate the disease, condition or disorder.

A patient may have a treatment-resistant disorder. Treatment-resistant means that the patient has not achieved adequate improvement after at least two adequate treatment courses. Specifically, the patient has not achieved adequate improvement after at least two adequate treatment courses, at least one of which is pharmacotherapy. For example, the patient has not achieved adequate improvement after at least two adequate pharmacotherapy courses. Specifically, in the current depressive episode, if the patient suffers from a disorder characterized by a current depressive episode, at least two previous treatment courses have been administered during the current episode.

As used in the context of this invention, "suicidal ideation" refers to thinking about, considering, or planning suicide. A physician or psychologist will diagnose a patient with suicidal ideation using established protocols and methods for assessing suicidality. Simply believing a patient is experiencing suicidal ideation is generally not sufficient. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of suicide or to have "actionary intent."

As used in the context of the present invention, unless otherwise stated, the term 'therapeutically effective amount' means that amount of an active compound or pharmaceutical ingredient that elicits a biological or clinical response in a human being sought by a researcher, physician or other clinician, including alleviation of signs and/or symptoms of the disease, condition or disorder being treated.

‘Clinical response’ includes, but is not limited to, improvement in assessment scales.

The severity of the condition, as well as changes in severity, can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and treatment efficacy.

The Clinical Global Impressions Scale (CGI) was developed to provide a brief, independent assessment of the clinician's view of the patient's overall functioning before and after treatment (Busner, J. and Tagrum, S. D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

The Clinical Global Impression-Severity (CGI-S) scale is based on a single question that clinicians must answer: “Considering your entire clinical experience with this particular population, how mentally ill is the current patient?” This is rated on a 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = slightly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill patients.

The CGI-S can be used to evaluate treatment success by comparing pre- and post-treatment scores.

Alternatively, treatment success can be assessed using the similarly simple CGI-Improvement Scale (CGI-I). After treatment, clinicians compare the patient's overall clinical condition with their pre-treatment condition (the so-called baseline). Again, there is only one question, rated on a 7-point scale: 'Compared to the patient's condition at admission to the project (before starting medication), has this patient's condition been as follows: 1 = Much improved since starting treatment; 2 = Much improved; 3 = Minimally improved; 4 = No change from baseline (starting treatment); 5 = Minimally worse; 6 = Much worse; 7 = Much worse since starting treatment.'

The Patient Global Impression scale (PGI), also known as the Subject Global Impression (SGI), is a counterpart to the Clinical Global Impression scale (CGI). It consists of a single item based on the CGI and adapted for patients. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

The severity of the condition, as well as the change in severity, can be further assessed by grading scales applicable to the specific mental or neurological disorder the patient suffers from.

Specific disease features can be assessed using individual items of the scale as well as sub-combinations of individual items as described herein.

Maternal function can be assessed using the Barkin Index of Maternal Functioning (BIMF).

When assessing clinical response at earlier time points (e.g., 2 hours) after drug administration based on endpoints developed for longer recall periods (e.g., typically 7 days for MADRS), reasonable modifications of these endpoints (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration) may be applied.

The considerations described above also apply at the early time point, since, on the one hand, the influence of the patient's condition before treatment on the scores recorded after treatment must be kept as low as possible to assess the clinical response, but on the other hand, sleep items cannot be assessed more than 2 hours after drug administration.

For example, at later time points beyond Day 1, all items on the relevant scale can be assessed using an adapted recall period, if necessary, to assess clinical response, eliminating the need for a pretreatment score. For example, if BIMF is assessed on Day 7, a 7-day recall period would be used (instead of the standard 2-week recall period).

Unless otherwise specified, the term "administration" (or "application") as used in the context of the present invention shall mean the introduction of an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient to a patient via any route. The active compound is administered intravenously, intramuscularly, or subcutaneously.

As used in the context of the present invention, unless otherwise stated, the terms 'dose' and 'dosage' (dosage amount) may refer to the amount of active compound or drug substance administered to a patient in an individual administration. The term 'dosage regimen' (or 'dosage regimen') shall mean a set sequence of one or more individual administrations.

Mental and nervous system disorders

The mental and neurological disorders to be treated according to the present invention have in common that they are associated with one or more symptoms from the symptom clusters discussed below, including sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

In one aspect, the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a lactating patient diagnosed with a mental or neurological disorder.

Mental or neurological disorders can be treated with 5-MeO-DMT or its pharmaceutically acceptable salts. These include major depressive disorder, persistent depressive disorder, bipolar disorder, anxiety disorders, post-traumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorders, and psychoactive substance abuse.

In a preferred embodiment, the mental disorder is major depressive disorder.

In another preferred embodiment, the mental disorder is postpartum depression (PPD), a complex mix of physical, emotional, and behavioral changes that occur in some women after childbirth. PPD is also known as major depressive disorder, which develops around the time of delivery. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), PPD is diagnosed when symptoms of major depressive disorder (MDD) begin during pregnancy or within four weeks after delivery.

In another preferred embodiment, the mental disorder is bipolar disorder, such as bipolar II disorder. In particular, the patient diagnosed with bipolar disorder is currently experiencing a major depressive episode.

Various aspects of bipolar disorder can be improved, including sleep disturbances, psychomotor retardation (decreased energy and activity, and decreased motivation), negative thinking (feelings of worthlessness, helplessness, and hopelessness, and guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or isolation (anhedonia, emotional withdrawal, and emotional blunting). Additional aspects of the disorder that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms, irritability, instability, increased motor drive, increased speech, and agitation). The improvements that can be achieved are reflected in clinically relevant measures.

Scales for assessing mental and neurological disorders

Numerous scales have been proposed to assess the severity of mental or neurological disorders. These scales are based on tests that can be self-administered or administered by a clinician.

Scales for assessing mental or neurological disorders that may be used in accordance with the present invention include scales known in the art for diagnosing and/or monitoring mental or neurological disorders, which are discussed in more detail below.

Treatment outcomes are assessed using one or more indicators or scales at one or more time points after completion of the treatment course.

An assessment can be performed after the acute hallucinatory experience has subsided. The appropriate time for an early assessment is typically approximately two to three hours after the last dose. For example, an early assessment can typically be performed approximately two or three hours after the last dose.

However, assessment of the effect on sleep disturbance or the effect on mental or neurological disorders related to the effect on sleep disturbance may be performed as early as possible after treatment ( i.e. , day 1), to ensure that the treated patient has the opportunity to sleep for at least one night.

Therefore, the assessment on day 1 or day 1 refers to the assessment on the day following administration. The assessment is performed 12 hours after the last dose, and in any case, one night after the last dose, and no later than 36 hours after the last dose. The assessment can be performed approximately 24 hours later.

An assessment on day 7 or day 7 means an assessment on day 7 after dosing (day 0 is the day of dosing). Similar definitions apply to other assessment periods measured in days.

For example, when assessing clinical response using one of the scales for assessing the severity of a psychiatric or neurological disorder, reasonable modifications of such endpoints (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration) may be applied at an earlier time point after drug administration based on endpoints developed over a longer recall period (e.g., typically 7 days for MADRS). The same applies to any other scale applied herein for assessing treatment effects for psychiatric or neurological disorders, unless the recall period is specifically indicated.

The considerations described above also apply at the early time point, since, on the one hand, the influence of the patient's condition before treatment on the scores recorded after treatment must be kept as low as possible to assess the clinical response, but on the other hand, sleep items cannot be assessed more than 2 hours after drug administration.

At later time points, for example, on day 1 or later, all items of the relevant scale typically needed to assess clinical response can be assessed using an adjusted recall period, eliminating the need to carry forward any pre-treatment scores.

Activator

Mental and neurological disorders represent a significant burden of illness and are characterized by multiple manifestations that can be appropriately treated. Therefore, treatment, particularly pharmacological interventions, is needed to improve not only overall disease scores but also specific aspects of the disorder.

The inventors believed that carefully selected hallucinogens could lead to improved treatment and, furthermore, overall improvements in disease and maternal function.

The inventors further posit that carefully selected hallucinogens may enable the continuation of breastfeeding without substantial interruption in the treatment of nursing mothers suffering from mental or neurological disorders.

One group of hallucinogens involves compounds that bind to the 5-hydroxytryptamine (5-HT) receptor, also referred to as serotonin receptors (seven families, 5-HT1 to 5-HT7, and several subtypes have been described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agonists are often referred to as "psychedelics," which emphasizes their primary ability to induce qualitatively altered states of consciousness, such as euphoria, trance, time-space transcendence, spiritual experiences, dissolution of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

Chemically, serotonergic hallucinogens are phenylalkylamines or indoleamines, and the indoleamine family is divided into two subgroups, ergolines and tryptamines, the latter derived from tryptamines.

Different serotonergic hallucinogens have different binding affinities and activating potencies for different serotonin receptors, particularly 5-HT1A, 5-HT2A and 5-HT2C, and their activity may also be modulated by interactions with other targets such as monoamine transporters and trace amine-associated receptors.

Recent published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using the shamanic drink ayahuasca, which contains DMT) for certain mental disorders suggest that these compounds may offer alternatives to currently available treatments. However, there are reports that these compounds can induce mania in patients with depressive symptoms, which may limit their clinical use.

For example, Lake et al. (Lake, C. R., Stirba, A. L., Kinneman, R. E. Jr., Carlson, B., Holloway, H. C., 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9)] report on a patient who experienced a manic episode after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication, which resolved but were followed approximately 3 weeks later by a manic episode of typical psychotic magnitude. Hendin and Penn (Hendin, H.M., Penn, A.D., 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3)] report an episode of mania following self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, A.G., Valerio, M.P., and Jose M Smith, J.M., 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4)] report a man with bipolar disorder who switched to mania after consuming ayahuasca, a drink containing DMT.

Additional case reports can be found in [Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49 (4), 294-296].

The present inventors considered that the compound to be administered should be appropriately selected, preferably administered in a specific dosage regimen, to avoid inducing mania or hypomania or at least reduce the risk of inducing mania or hypomania.

The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a hallucinogen of particular interest for therapeutic use. 5-MeO-DMT possesses a unique pharmacological profile distinct from that of other hallucinogenic compounds.

5-MeO-DMT is a potent, short-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype compared to other classic hallucinogens.

The inhibitory constants (K _i values) for psilocin (the dephosphorylated form of psilocybin formed after absorption of psilocybin), DMT and 5-MeO-DMT, as described in more detail in the Examples section below, are 48, 38 and 1.80 nM, respectively, at 5-HT1A receptors located in the hippocampus of postmortem human brain. Thus, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity for 5-HT1A receptors. The inhibitory constants (K _i values) for psilocin, DMT and 5-MeO-DMT are 37, 117 and 122 nM, respectively, at 5-HT2A receptors located in the prefrontal cortex of postmortem human brain. Thus, psilocin exhibits intermediate/strong affinity, while DMT and 5-MeO-DMT exhibit relatively weak affinity for 5-HT2A receptors.

Compared to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, making it a potent agonist. For psilocin and DMT, the contribution of 5-HT2A binding is increased compared to 5-MeO-DMT, with the latter exhibiting the greatest differential affinity for 5-HT1A compared to 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a significantly greater role in the overall effects of 5-MeO-DMT than 5-HT2A binding compared to the other two compounds.

While 5-HT1A agonism has been reported to reduce impulsivity and aggression, 5-HT2A agonism can briefly increase these same traits. Furthermore, the dopaminergic system is implicated in contributing to mania, and increased dopaminergic drive has been linked to mania. LSD, psilocybin, and DMT all exhibit increased affinity for various dopamine receptors compared to 5-MeO-DMT.

Compared to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered to patients suffering from mental or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder [MDD], postpartum depression [PPD], persistent depressive disorder, seasonal affective disorder and bipolar disorder [BD], such as bipolar I disorder and bipolar II disorder; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder, preferably using the dosing regimens described herein, without a significant risk of inducing mania or hypomania in patients. Patients suffering from such mental or neurological disorders treated according to the present invention do not experience treatment-emergent mania or hypomania.

It is also noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate that large quantities of each compound (e.g., DMT/ayahuasca, psilocybin, LSD) were used.

Our approach to sequential dose escalation of 5-MeO-DMT significantly reduces the risk of overdosing with the associated potential for adverse events.

Moreover, the induction of isolated hypomania by antidepressants has been reported in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD found no evidence of hypomania induction.

5-MeO-DMT can induce a peak experience, i.e., an altered emotional perspective often described as a "loss of self" culminating in an overwhelming "oneness with the universe," more rapidly than other hallucinogens, and has a shorter duration of acute hallucinogenic effects (e.g., 5 to 30 minutes after intravenous injection, compared to several hours for oral psilocybin and oral LSD). These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile that may be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

Moreover, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. We determined a K _i of 2.3 nM using recombinant human 5-HT7 receptor, [ ³ H]LSD as a radioligand, and serotonin to estimate nonspecific binding.

Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

The 5-HT7 receptor plays a crucial role in neurogenesis, synaptogenesis, and dendritic spine formation. It is involved in central processes such as learning and memory, sleep regulation, circadian rhythms, and pain perception, among others.

5-HT7 receptors are expressed particularly in Purkinje neurons of the hypothalamus, hippocampus, prefrontal cortex, striatum complex, amygdala, and cerebellum, including the spinal cord, raphe nucleus, thalamus, and suprachiasmatic nucleus.

The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It regulates circadian rhythms across various brain regions. Disruption of this regulation may lead to disease states, particularly those involving sleep disturbances. In patients with sleep disorders, resting-state functional connectivity analyses reveal altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode neural network.

The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the receptor's function in regulating the sleep/wake cycle. The inventors believe that 5-MeO-DMT, which acts on these receptors, could be used to treat patients with sleep disorders.

The present inventors consider that the binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT involves a 'resetting' of the functional connectivity of neural networks and neuroplastic effects, which contribute to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

The inventors further contemplate that the binding of 5-MeO-DMT to 5-HT1A receptors as well as 5-HT7 receptors as two mediators of the effects exerted by 5-MeO-DMT, including functional connectivity 'resetting' of neural networks and neuroplastic effects, may also result in beneficial effects in patients suffering from other symptoms or conditions such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social/emotional withdrawal. This is supported by the clinical results demonstrated in the trials referred to herein.

Another characteristic of 5-MeO-DMT is its short half-life.

5-MeO-DMT is inactivated primarily through a deamination pathway mediated by monoamine oxidase A, which is then O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

The present inventors investigated the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after administration.

Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. As early as 10 minutes after administration, concentrations drop to less than 10% of Cmax, 2 hours later, they are less than 1% of Cmax, and 3 hours later, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated administration within a time frame of 1 to 4 hours. Dose escalation, as described herein, does not lead to accumulation; for example, no further increases in plasma concentrations occur 10 minutes, 2 hours, or 3 hours after administration.

The inventors further confirmed that 5-MeO-DMT offers several properties that make it an attractive treatment for PPD. Unlike SSRIs, it is a rapid-acting agent (in the 5-MeO-DMT-TRD trial, 5 of 8 patients with TRD achieved remission within 2 hours of dosing, 8 of 8 patients achieved remission on day 1, and 7 of 8 patients maintained their remission on day 7). Treatment of PPD patients with 5-MeO-DMT can achieve rapid improvements in both depressive symptoms and maternal function. Furthermore, 5-MeO-DMT is administered in a single treatment session and can be readministered infrequently, distinguishing it from SSRIs, which require chronic daily dosing regimens associated with poor compliance, and from brexanolone, which requires long-term infusions and hospitalization.

Therefore, the present invention also addresses compliance and patient convenience.

Moreover, the inventors have shown that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows continued breastfeeding with only a brief interruption for treatment.

According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used. When the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is mentioned, the use of isotopic variants is also contemplated.

These variants are particularly the deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of these forms.

The deuterated form of 5-MeO-DMT has a higher deuterium content than expected based on the natural abundance of this isotope.

The deuterated form of 5-MeO-DMT is a form in which deuterium is introduced specifically at one or more defined hydrogen positions.

Examples of deuterated forms of 5-MeO-DMT include, without limitation, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

Additional examples include 5-MeO-DMT forms in which deuterium is introduced at one or more hydrogen positions of the N-linked methyl group. Further examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms in the indole ring system. It should be noted that combinations of the above substitution patterns are also contemplated.

Methods for preparing these compounds are known in the art.

According to the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms and non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of these salts, as well as mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT can also be used.

Additionally, according to the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in molar amounts equal to the amount of the corresponding non-deuterated form.

According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. These 5-MeO-DMT prodrugs can be metabolically converted to 5-MeO-DMT. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of the 5-MeO-DMT prodrug or a salt thereof may be replaced with the use of the 5-MeO-DMT prodrug or a salt thereof.

In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced by an organic moiety that can be cleaved after administration.

Examples of suitable organic moieties are -C(O)OR ¹ , -C(O)R ² , -CH(R ³ )OR ⁴ , -C(O)OCH(R ³ )OC(O)R ⁴ , -C(O)OCH(R ³ )OC(O)OR ⁴ , -CH(R ³ )C(O)R ⁴ , -CH(R ³ )OC(O)R ⁴ , -CH(R ³ )OC(O)OR ⁴ , wherein each of R ¹ , R ² , R ³ , and R ⁴ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

Preferred examples of organic moieties include -CH(R ³ )OC(O)R ⁴ and -C(O)OR ¹ , where R ¹ , R ³ , and R ⁴ are defined above.

Prodrugs, especially those of the above structure, can also be used in the form of pharmaceutically acceptable salts.

A specific example of a prodrug is 5-MeO-DMT carboxy-isopropyl valerate, preferably in salt form, and in particular ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate di-trifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

Methods for preparing prodrugs such as those discussed herein are known in the art.

According to the present invention, the T _max value of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg/kg is preferably 1 hour or less, more preferably 0.7 hour or less, and especially 0.5 hour or less.

Additionally, according to the present invention, the prodrug of 5-MeO-DMT and the salt of the prodrug of 5-MeO-DMT are used in the same molar amount as the amount of the corresponding non-prodrug form.

Dosage method

Therapeutically effective doses of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. These routes of administration ensure rapid onset of action. The most preferred route of administration is intravenous, i.e., intravenous injection.

5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration by injection, examples of excipients and vehicles for such formulations being known in the art.

Dosage regimen

The present invention also provides dosage ranges, specific doses, as well as dosing regimens (dosage plans) and suitable routes of administration.

The present invention is based in part on the inventors' conclusion that the occurrence of a peak hallucinatory experience during the acute phase following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as a surrogate behavioral marker for a causal or at least underlying unknown therapeutic mechanism drives therapeutic benefit in patients as defined herein diagnosed with one or more of the above-defined aspects, including treatment-resistant forms of the disorders as defined herein and such disorders associated with suicidal ideation.

Consequently, a better therapeutic profile will be achieved with a faster peak experience in a greater proportion of patients and better reproducibility within individual patients compared to previously tested hallucinogens, dosing regimens and routes of administration.

Additionally, the present invention also relies on the short duration of action of 5-MeO-DMT and the associated absence of tolerance (i.e., diminishing or absent hallucinogenic effects after re-administration), allowing for a dosing regimen with frequent re-administrations (e.g., more than once daily or daily), which are designed to increase the incidence of peak experiences and thus increase therapeutic benefit. Such repeated dosing within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdose, which may otherwise lead to physical side effects such as serotonin syndrome, negative psychological reactions such as recurrence of hallucinatory experiences at later time points, induction of mania or hypomania, or less meaningful hallucinatory experiences with little or no memory of the altered state (so-called 'whiteouts'). Additionally, starting with a low dose allows the patient to become accustomed to the hallucinatory experience overall and prepares them for the development of more intense symptoms at higher doses, which will positively influence the experience at these higher doses. Additionally, the prospect of initiating treatment at lower doses will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

Frequent re-administration of serotonergic hallucinogenic drugs with the aim of increasing the rate of peak experiences, adjusting their reproducibility, improving therapeutic effects, reducing side effects and improving compliance rates may be impossible when used with other hallucinogenic drugs due to the late onset and long duration of hallucinogenic effects and the rapid development of tolerance (i.e., reduced or absent hallucinogenic effects after re-administration), which can last for several days.

A patient as defined herein diagnosed with a treatment-resistant form of a disorder as defined herein, including such a disorder associated with suicidal ideation, treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e., the patient is not receiving any other treatment for the diagnosed disorder.

The dosage of 5-MeO-DMT to be administered to a patient as defined herein diagnosed with a treatment-resistant form of a disorder as defined herein and including such disorders associated with suicidal ideation is any amount in the range of about 1 mg to about 10 mg or a range therein, administered in the form of a dosage form based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, which weight amount can be calculated from the specified weight amount of 5-MeO-DMT free base assuming equimolar amounts are used. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. When a range is presented in this specification, such as 'about 1 mg to about 10 mg', the inventors contemplate all discrete values within that range, some of which are specifically mentioned, but not all of which are mentioned - this is simply for the sake of brevity.

In a preferred embodiment, the improved method for treating a patient as defined herein diagnosed with a disorder as defined herein, including a treatment-resistant form of such disorder and including a disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response within about 2 hours after administration of 5-MeO-DMT.

In a preferred embodiment, the improved method for treating a patient as defined herein diagnosed with a treatment-resistant form of a disorder as defined herein and such disorder associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT, comprises a clinical response, including a clinical response that occurred within about 2 hours after administration of 5-MeO-DMT, persisting for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

In a preferred embodiment, an improved method for treating a patient as defined herein diagnosed with a treatment-resistant form of a disorder as defined herein and such disorder associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT, comprises administering more than a single dose of 5-MeO-DMT.

In a preferred embodiment, this single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with at least about 1 hour and no more than about 24 hours between administrations within each treatment block, and with at least about 6 days between the end of one treatment block and the start of the next treatment block.

In a more preferred embodiment, this single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of one to three administrations, with about 24 hours between each administration within each treatment block, and with at least about 6 days between the end of one treatment block and the start of the next treatment block.

In a most preferred embodiment, such single dose administration of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of one to three administrations, with about one to four hours, preferably one to two hours, between each administration within each treatment block, and with about six or more days between the end of one treatment block and the start of the next treatment block.

In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until 10 mg is reached or until all administrations within that treatment block have been administered, whichever comes first.

In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until 10 mg is reached or until all administrations within that treatment block have been administered, whichever is sooner, or until the patient experiences the peak psychedelic experience or the supervising physician determines that further dosage increases are inappropriate based on observed side effects.

In embodiments where the dosage is increased for subsequent administrations, the dosage for the subsequent administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage of the previous administration. For example, if the dosage for the first administration was 1 mg and the dosage increase is 3 mg, the dosage for the second administration would be 4 mg, unless one of the previously mentioned discontinuation criteria is reached. Preferably, the dosage for the third administration would be 7 mg.

In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, then increased to a selected dosage of about 4 mg to about 6 mg for the second administration and then increased to a selected dosage of about 7 mg to about 9 mg for the third administration, unless the patient has already had the peak psychedelic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects. Useful specific amounts for the first, second and third administrations are, for example, about 2 mg, about 5 mg and about 8 mg.

In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has already had the peak psychedelic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects. Useful specific amounts for the first, second and third administrations are, for example, about 1 mg, about 2 mg and about 3 mg.

Also in a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1.5 mg to about 2.5 mg for the first administration, then increased to a dosage selected from about 3.5 mg to about 4.5 mg for the second administration and from about 5.5 mg to about 6.5 mg for the third administration, unless the patient has already had the peak psychedelic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects. Useful specific amounts for the first, second and third administrations are, for example, about 2 mg, about 4 mg and about 6 mg.

In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2.5 mg to about 3.5 mg for the first administration, then increased to a dosage selected from about 4.5 mg to about 5.5 mg for the second administration and from about 6.5 mg to about 7.5 mg for the third administration, unless the patient has already had the peak psychedelic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects. Useful specific amounts for the first, second and third administrations are, for example, about 3 mg, about 5 mg and about 7 mg.

In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 3 mg for the first administration, then increased to a selected dosage of about 4.5 mg to about 5.5 mg for the second administration and then increased to a selected dosage of about 7 mg to about 8 mg for the third administration, unless the patient has already had the peak psychedelic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects. Useful specific amounts for the first, second and third administrations are, for example, about 2.5 mg, about 5 mg and about 7.5 mg.

In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased for each subsequent administration within that first treatment block until 10 mg is reached or until all administrations within that treatment block have been administered, whichever is sooner, or until the patient experiences a peak hallucinatory experience or the supervising physician determines that further dose increases are inappropriate based on observed side effects, whichever is sooner, and the highest dosage in the first treatment block is used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. For example, if the highest dosage in the first treatment block is 8 mg, then the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block will be 8 mg because the patient experienced a peak hallucinatory experience at this dosage.

In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first administration block, then increased to a selected dose from about 4 mg to about 6 mg for the second administration of the first administration block, and then increased to a selected dose from about 7 mg to about 9 mg for the third administration of the first administration block, unless the patient has already had the peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage of the first treatment block being used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. Useful specific amounts for the first, second and third administrations within the first treatment block are, for example, about 2 mg, about 5 mg and about 8 mg.

In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of a first administration block, then increased to a selected dosage from about 1.5 mg to about 2.5 mg for the second administration of the first administration block, and then increased to a selected dosage from about 2.5 mg to about 3.5 mg for the third administration of the first administration block, unless the patient has already had the peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage of the first treatment block being used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. Useful specific amounts for the first, second and third administrations within the first treatment block are, for example, about 1 mg, about 2 mg and about 3 mg.

In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first administration block, then increased to a selected dose from about 3 mg to about 5 mg for the second administration of the first administration block, and then increased to a selected dose from about 5 mg to about 7 mg for the third administration of the first administration block, unless the patient has already had the peak hallucinogenic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects, with the highest dosage of the first treatment block being used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. Particular useful amounts for the first, second and third administrations of a first treatment block are, for example, about 2 mg, about 4 mg and about 6 mg.

In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 4 mg for the first administration of a first administration block, then increased to a selected dose from about 4 mg to about 6 mg for the second administration of the first administration block, and then increased to a selected dose from about 6 mg to about 8 mg for the third administration of the first administration block, unless the patient has already had the peak hallucinogenic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects, with the highest dosage of the first treatment block being used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. Particular useful amounts for the first, second and third administrations of a first treatment block are, for example, about 3 mg, about 5 mg and about 7 mg.

In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1.5 mg to about 3.5 mg for the first administration of a first administration block, then increased to a selected dose from about 4 mg to about 6 mg for the second administration of the first administration block, and then increased to a selected dose from about 6.5 mg to about 8.5 mg for the third administration of the first administration block, unless the patient has already had the peak hallucinogenic experience within that treatment block or the supervising physician determines that further dosage increases are inappropriate based on observed side effects, with the highest dosage of the first treatment block being used as the dosage for all subsequent treatment blocks and administrations within that subsequent treatment block. Particular useful amounts for the first, second and third administrations of a first treatment block are, for example, about 2.5 mg, about 5 mg and about 7.5 mg. Pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosage regimens, and it is understood that the appropriate weight amount of salt to be administered can be calculated from the stated weight of the free base, assuming that equimolar amounts are used.

According to the present invention, 5-MeO-DMT is preferably not administered together with an MAO inhibitor.

The occurrence of a 'peak hallucinatory experience' in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystery, positive mood, time-space transcendence, and indescribability) of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (as described in the literature [Barrett FS, J Psychopharmacol. 2015;29(11):1182-90]).

The occurrence of a 'peak hallucinatory experience' in a patient can also be identified by the achievement of at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in the literature [Roseman L et al., Front Pharmacol. 2018; 8:974]).

According to the present invention, the occurrence of a 'peak hallucinatory experience' in a patient is preferably identified by the achievement of a score of at least 75 on the Peak Experience Scale [PES] total score, also referred to as the Peak Hallucinatory Experience Questionnaire [PPEQ], which is the average of the patient's answers scored from 0 to 100 to the following three questions: 1. How intense was the experience; 2. To what extent did you lose control; and 3. How profound (i.e., deep and significant) was the experience?

sleep disorders

Sleep has two basic types: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I–IV). These non-REM stages correspond to increasing sleep depth. Non-REM and REM sleep alternate each night during each of the four to five cycles of normal human sleep. During the early part of the night, non-REM sleep is deeper and accounts for a disproportionately large portion of the time, particularly within the first cycle. As the night progresses, non-REM sleep becomes shallower, and more of each cycle is devoted to REM sleep.

Normal, healthy sleep consists of different stages that occur sequentially in a strictly regulated sequence throughout the night, as described above.

Disruption of this strict regulation results in sleep disturbances.

Sleep disorders, whether idiopathic or occurring within the context of a medical condition such as a psychiatric or neurological disorder, are conditions that affect the quality, timing, or duration of sleep. These conditions affect a person's ability to function properly while awake.

Common forms of sleep disorders include disturbances in initiating and maintaining sleep (insomnia), disturbances of excessive sleepiness (hypersomnia), disturbances of the sleep-wake schedule (circadian rhythm disorders), dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnias), disorders characterized by disturbances in breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

Insomnia is a sleep disorder in which people have difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep, wake up frequently during the night and have difficulty falling back asleep, wake up too early in the morning, have unrefreshing sleep, or have at least one daytime problem due to poor sleep, such as fatigue, drowsiness, mood problems, trouble concentrating, or accidents at work or while driving.

Hypersomnia is characterized by excessive daytime sleepiness and/or prolonged nighttime sleep. A state of sleepiness is also observed in patients with hypersomnia. They experience difficulty transitioning from sleep to wakefulness. Individuals experiencing sleepiness report awakenings accompanied by confusion, disorientation, slowness of movement, and repeated attempts to return to sleep.

Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances due to alterations in an individual's internal circadian rhythm or due to a misalignment between the circadian rhythm and desired or required work or social schedules. This asynchrony can be temporary or persistent. The resulting clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are typically shortened and interrupted, performance during the desired waking state is impaired, and temporary opportunities to return to a regular sleep schedule are missed.

Parasomnias are a diverse group of sleep disorders characterized by unusual behaviors or physiological events (e.g., sleepwalking or nightmares) experienced just before falling asleep, during sleep, or during the wakeful period between sleep and wakefulness. They vary considerably in their characteristics, severity, and frequency. Parasomnias can impair sleep quality.

Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of respiratory muscles and the brain's regulatory centers. One form of sleep-related breathing disorder is central sleep apnea, which occurs when the brain stops sending signals to control breathing, based on underlying health conditions. Central sleep apnea can have significant implications for sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, leading to fragmented sleep with microarousals or awakenings. This can result in excessive daytime sleepiness.

In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements interfere with sleep or its onset. The most common are restless leg syndrome (RLS) and periodic limb movement disorder (PLMD).

Inadequate sleep quantity and quality can lead to personality changes, exacerbating existing mental health conditions and even triggering the development of mental health disorders. Sleep disturbances can impair cognitive function and even lead to memory impairment. Those who are sleep-deprived may experience difficulty making decisions, irritability, performance difficulties, and slow reaction times. Sleep deprivation can also negatively impact one's quality of life by contributing to the development of obesity, diabetes, and heart disease.

Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatments. If treatment is unsuccessful, medication or psychotherapy may also be used.

Available treatments are not successful for all patients, may be associated with side effects, and/or may require long-term treatment to achieve the desired therapeutic effect.

In patients with sleep disturbances associated with mental or neurological disorders, known treatments for the mental or neurological disorder do not necessarily improve the sleep disturbances.

For example, sleep disturbances are often associated with mental disorders such as depression. However, treating depression does not necessarily improve the accompanying sleep disturbances. While most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while others can cause sleep disturbances.

While sleep disturbances can be considered a condition requiring treatment regardless of any other medical conditions, disorders, or symptoms an individual may suffer from, several mental and neurological disorders are associated with sleep disturbances. Notably, the relationship between sleep and mental or neurological disorders is often bidirectional. Not only can mental or neurological disorders negatively impact healthy sleep patterns, but sleep disturbances can also be a contributing factor to the onset, progression, and prognosis of mental or neurological disorders.

The treatment according to the present invention reduces or eliminates sleep disturbances and preferably also improves associated mental or neurological disorders.

Measurement of sleep disturbances

Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of awakenings throughout the night. Quantitative indicators can be measured objectively, including polysomnography, actigraphy, and sleep latency determinants, or through self-reported measures (questionnaires).

Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic. It measures various functions throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movement, snoring, and heart rate.

Another quantitative measurement is an actimetry device. This device measures motor activity by wearing an actimetry sensor, which is then continuously recorded to assess sleep-wake cycles. This technology allows patients to continue with their normal daily routine while recording the necessary data in a natural sleep environment.

Sleep latency can be measured using the Multiple Sleep Latency Test (MSLT). This test provides an objective measure of how long it takes a person to fall asleep over several test naps. An average sleep latency of approximately 10 minutes is considered normal; less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Concomitant analysis of brain activity can help further diagnose sleep disorders.

The Sleep Rating Questionnaire captures assessments of sleep quality components such as perception of sleep depth, difficulty waking, and post-sleep comfort, in addition to other factors that can affect sleep quality, such as comorbid conditions and medication use. Because sleep disorders often persist despite normal values on quantitative measures of sleep, assessing the qualitative aspects of the sleep experience is crucial.

Questionnaires not only facilitate rapid and accurate assessment of complex clinical problems, but can also potentially be helpful in tracking patient progress.

Various sleep quality indices are known. The following indices include questionnaires for assessing general sleep quality and questionnaires specifically for assessing insomnia, hypersomnia, circadian rhythm disturbances, and parasomnias. However, the present invention is not limited to the use of any specific indices or questionnaires.

Some questionnaires rely on a recall period (recall time window) of several days or even weeks. While this may be appropriate for diagnosing sleep disorders, it is not always appropriate for assessing treatment effects, especially those with rapid onset. For many questionnaires, the recall period can be modified to reflect the post-treatment period. The questionnaires specifically discussed herein for assessing treatment effects on sleep in patients with certain conditions rely on a recall period that begins no earlier than the time when acute hallucinations have subsided after the last dose. To meet this criterion, the commonly applied recall period is modified, if necessary.

For example, the Sleep-50 questionnaire can be used to assess overall sleep quality.

The Sleep-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. It consists of nine subscales reflecting the most common sleep-related disorders and disorders, some of which are sleep apnea, as well as diagnostic factors such as insomnia, narcolepsy, restless legs/periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, and the impact of sleep disorders on daily functioning. For each item, respondents are provided with a scale ranging from 1 ('not at all') to 4 ('very much') and asked to indicate the extent to which the statement matches their experiences over the previous month or another appropriate recall window.

To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cut-off point, but respondents must also meet a cut-off of at least 3 or 4 ('somewhat a lot' or 'very much', respectively) on the subscale assessing the impact of sleep complaints on daily functioning (Spoormaker et al. , Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46]).

Treatment success is indicated by (i) a reduction in score, preferably (ii) a reduction below the cut-off value.

A common questionnaire for assessing sleep disturbances is the Pittsburgh Sleep Quality Index (PSQI). Other tools include the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System ( ^PROMIS® ) Sleep Disturbance Scale.

The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a 19-item self-assessment questionnaire. Respondents are asked to indicate how often they experienced certain sleep difficulties over the past month or another appropriate recall period.

Nineteen self-assessment items assess various factors related to sleep quality, including estimates of sleep duration and latency, and the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

Each component is assigned a score from 0 to 3, with higher scores indicating more severe sleep disturbances. Detailed scoring guidelines for the Pittsburgh Sleep Quality Index can be found in Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

The seven component scores are then summed to produce a single overall score ranging from 0 to 21, with a score of 0 indicating no difficulty and a score of 21 indicating severe difficulty across all domains. A global score cutoff of 5 distinguishes good sleepers from poor sleepers. A global score greater than 5 indicates that the patient is experiencing severe difficulty in at least two domains or moderate difficulty in three or more domains.

When treatment outcome is assessed using the PSQI, treatment success is indicated by (i) a decrease in score, preferably (ii) a decrease to less than 5.

The Insomnia Severity Index (ISI) is a short questionnaire that assesses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning, how significantly the respondent perceives insomnia compared to others, and the overall level of distress generated by sleep problems. Individual responses are scored from 0 (none) to 4 (very much), with higher total scores indicating more severe insomnia. A total score of 0 to 7 indicates “no clinically significant insomnia,” 8 to 14 indicates “subthreshold insomnia,” 15 to 21 indicates “moderate clinical insomnia,” and 22 to 28 indicates “severe clinical insomnia” (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). The recall window is two weeks. Other appropriate recall windows may also be used.

Treatment success is indicated by (i) a decrease in score, e.g., by more than 7 points, especially by more than 8 points; preferably (ii) a decrease below the cut-off value for clinically significant insomnia.

The Sleep Disturbance Questionnaire (SDQ) assesses subjective experiences of insomnia. By assessing anxiety/agitation, mental hyperactivity, the consequences of insomnia, and poor sleep preparation, the SDQ specifically addresses beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate how often they experience specific statements about insomnia, with 1 indicating "not at all" and 5 indicating "very often." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (reviewed by A. Shahid et al., supra).

Treatment success is indicated by a decrease in scores.

The Patient-Reported Outcomes Information System (PROMIS) ^® Sleep Disturbance Inventory is a universally accepted measure for assessing sleep disturbances. Available as a long form and four different short forms (e.g., 4-, 6-, and 8-item versions), it assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulty in obtaining or maintaining sleep over a 7-day period.

Each item on the scale is rated on a 5-point scale. The raw scores for each item are summed to obtain a total raw score. This total raw score is then converted to a standardized T-score using a conversion table.

Treatment success is indicated by a decrease in T-score.

Hypersomnia or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity scale.

The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. It asks respondents to rate how likely they are to fall asleep in eight different situations, representing moments of relative inactivity, such as taking an afternoon nap or sitting in a car stopped in traffic. Respondents rate their likelihood of falling asleep using a 0- to 3-point scale (where 0 represents "never sleepy" and 3 represents "very likely sleepy"). Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 potentially identifies clinically significant daytime sleepiness (A. Shahid et al., supra).

Treatment success is indicated by (i) a reduction in score, preferably (ii) a reduction to 10 points or less.

The Stanford Sleepiness Scale (SSL) is a subjective measure of sleepiness that assesses sleepiness at a specific point in time. It consists of a single item, and respondents are asked to select one of seven statements that best describes their current level of perceived sleepiness. A scale ranging from 1 (feeling active and energetic; alert; fully awake) to 7 (almost dreamy; sleep onset imminent; difficulty remaining awake) is used to assess sleepiness (reviewed in A. Shahid et al., supra).

Treatment success is indicated by a decrease in scores.

Parasomnias can be assessed by the Paris Disorders of Arousal Severity Scale (PADSS).

The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnia behaviors, rates their frequency, and includes assessment of their consequences (Arnulf et al. , A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

Treatment success is indicated by (i) a decrease in score, preferably (ii) a decrease below the cut-off value.

A common questionnaire used to assess sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period can also be selected.

Treatment success is indicated by a decrease in scores.

A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale (IRSG). This 10-item questionnaire asks respondents to indicate how severely their disorder has affected them over the past week using a Likert-type rating scale. Questions can be divided into two categories: symptomatology (nature, intensity, and frequency) and impact (sleep problems, impairment in daily functioning, and resulting mood changes). Each of the 10 questions asks respondents to rate their experience of RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least severe symptoms. Total scores can range from 0 to 40. As a brief scale with excellent psychometric properties, this tool may be suitable for a variety of research and clinical purposes, including screening and assessing treatment outcomes (A. Shahid et al., supra).

Treatment response can be assessed by a decrease in scores.

Resting-state neural networks and sleep disorders

Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). Observed patterns that characterize a neural network of brain regions with consistent patterns of signal fluctuations are called resting-state networks (RSNs).

Various resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen primarily in task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks are characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various disease states. These disease states are associated with altered functional connectivity within specific resting-state neural networks and/or between one or more regions of one or more additional resting-state neural networks.

Altered resting-state neural networks can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

The primary neural network involved in sleep is the default mode network (DMN). Normally, the DMN is inactive during tasks and active during rest. It is involved in multiple cognitive processes, including higher cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, altered DMN activity is particularly relevant in the context of sleep disorders.

Degraded resting state neural networks may also be found in psychiatric or neurological disorders, as further discussed herein.

The resting-state neural networks involved in sleep disorders are also affected by mental or neurological conditions that are a consequence of certain medical health conditions.

In patients with insomnia, dysfunctional connectivity has been observed within the default mode neural network (DMN) and the salience network, which are involved in the detection and integration of emotional and sensory stimuli. Studies suggest that these networks contain important regions that integrate emotional and physical states, and that dysfunctional connectivity within and/or between these networks and other brain regions may contribute to patients' vigilance, subjective distress, and poor sleep continuity.

In patients with hypersomnia, the default mode neural network is affected. For example, in idiopathic hypersomnia, distinct DMN hubs—the precuneus and medial prefrontal cortex—show significant changes, and DMN functional connectivity correlates with self-reported sleepiness severity.

A study examining differences between night-shift and day-shift nurses revealed that circadian rhythm disruption contributes to altered resting-state function in the cerebellum, which is involved in sleep regulation, and cognitive functions such as reactivity and arousal. Furthermore, functional connectivity of the DMN differs fundamentally between early and late circadian phenotypes. Circadian rhythm disruption, like other forms of sleep disturbance, can lead to alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various disorders associated with circadian rhythm disruption.

Although functional brain imaging is technically difficult to perform during parasomnia episodes, precuneus differences have been observed in arousal disorders that present with non-REM parasomnias.

The precuneus is involved in the analysis and integration of visual, auditory, and somatosensory information, as well as in the monitoring of movement. It is a subregion of the DMN. Therefore, the default state neural network is affected in patients with parasomnia.

Resting-state fMRI studies of patients with sleep-related breathing disorders, such as central sleep apnea, reveal significant global and regional connectivity deficits, particularly in the default state neural network (DMN) and areas associated with arousal and sensorimotor systems.

For example, sleep-related motor disturbances, such as periodic limb movements during sleep, are reflected by changes in the prefrontal motor control pathway, a subregion of the default state neural network. Furthermore, increased activity in the cerebellum and thalamus, as well as in the red nucleus and brainstem, can be observed.

In many cases, the abnormal functional connectivity of the resting-state neural networks involved in sleep disorders is also implicated in the pathologies listed above. Therefore, according to the present invention, influencing these neural networks through the therapy according to the present invention will result in improvement of sleep disorders, and if the treated patient suffers from a psychiatric or neurological disorder, it will also result in improvement of those disorders.

Treatment of sleep disorders and mental and nervous system disorders

The present invention can treat not only idiopathic sleep disorders but also sleep disorders in patients suffering from mental or neurological disorders. In patients suffering from sleep disorders associated with mental or neurological disorders, treatment of sleep disorders according to the present invention results in improvement of the pathological conditions associated with the sleep disorder.

In many cases, the resting-state neural networks involved in sleep disorders are also involved in the conditions listed above.

5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting neural networks. This disruption reestablishes pathologically miswired brain connections as the neural network reconnects. New, healthy functional connections are established with lasting effects.

The persistence of its effects may be explained by the neuroplasticity-promoting properties of 5-MeO-DMT. Specifically , 5-MeO-DMT promotes structural and functional plasticity at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, initiating the formation of new synaptic connections. These new connections can be strengthened, weakened, or even eliminated depending on activity.

The new synapses that are ultimately formed ultimately influence the activity patterns of neurons. The inventors concluded that these mutual structural and functional modifications contribute to the proper establishment of neural networks and the persistence of the effects of 5-MeO-DMT administration.

From a biochemical point of view, 5-MeO-DMT interacts, inter alia, with 5-HT receptors.

5-HT receptors, receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A wide range of physiological and pathological functions are mediated through these receptors.

In the brain, seven types of 5-HT receptors are expressed, which can be further divided into several subtypes. The various types and subtypes exhibit distinct spatial distributions.

5-MeO-DMT interacts with multiple 5-HT receptors. These receptors are involved in mediating the effects of 5-MeO-DMT on resting-state neural networks and neural plasticity.

In addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist for this receptor, exhibiting high (nanomolar) binding affinity.

The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis, and dendritic spine formation. It is involved in central processes such as learning and memory, sleep regulation, circadian rhythms, and pain perception, among others.

5-HT7 receptors are expressed particularly in Purkinje neurons of the hypothalamus, hippocampus, prefrontal cortex, striatum complex, amygdala, and cerebellum, including the spinal cord, raphe nucleus, thalamus, and suprachiasmatic nucleus.

The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It regulates circadian rhythms across various brain regions. Disruption of this regulation may lead to disease states, particularly those involving sleep disturbances. In patients with sleep disorders, resting-state functional connectivity analyses reveal altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode neural network.

The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the receptor's function in regulating the sleep/wake cycle. The inventors believe that 5-MeO-DMT, which acts on these receptors, could be used to treat patients with sleep disorders.

The present inventors consider that the binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT involves a 'resetting' of the functional connectivity of neural networks and neuroplastic effects, which contribute to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

The inventors further contemplate that the binding of 5-MeO-DMT to 5-HT1A receptors as well as 5-HT7 receptors as two mediators of the effects exerted by 5-MeO-DMT, including functional connectivity 'resetting' of neural networks and neuroplastic effects, may also result in beneficial effects in patients suffering from other symptoms or conditions such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social/emotional withdrawal. This is supported by the clinical results demonstrated in the trials referred to herein.

The treatment according to the present invention results in an improvement in sleep disorders, and if the treated patient suffers from a mental or neurological disorder, it also results in an improvement in said disorder.

Clinical data from studies of patients with treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that administration of 5-MeO-DMT can successfully treat sleep disturbances.

In the TRD trial, described in more detail in the Examples section below, the MADRS item 'Sleep Decreased', which reflects insomnia in particular, was assessed.

The MADRS item "Reduced Sleep" indicates a decrease in the duration or depth of sleep compared to the subject's normal pattern when healthy. A score of 0 indicates a subject sleeping normally. A score of 2 indicates some difficulty falling asleep, or slightly reduced, light, or irregular sleep. A score of 4 indicates sleep was reduced or interrupted by at least 2 hours. A score of 6 indicates less than 2 or 3 hours of sleep.

In the study group receiving individualized dosing, the aggregate score for the MADRS item "Reduced Sleep" across all eight patients was 25 at baseline. On Day 1 post-treatment, the earliest time point at which the treatment's impact on sleep could be assessed, this had decreased to 12 points, representing a 13-point or 52% improvement. On Day 7 post-treatment, this had decreased to 9 points, representing a 16-point or 64% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Reduced Sleep' was 12 at baseline across all four patients. On day 1 post-treatment, this decreased to 10, representing a 2-point or 17% improvement. On day 7 post-treatment, this decreased to 6, representing a 6-point or 50% improvement.

Therefore, the score for "sleep reduction," a scale item particularly related to sleep disorders, was significantly improved. The present inventors concluded that 5-MeO-DMT can be used to treat sleep disorders, particularly in patients with psychiatric or neurological disorders.

cognitive dysfunction

Cognition encompasses the skills necessary for thinking, remembering, paying attention, and problem-solving. The loss or impairment of these skills results in cognitive dysfunction, a term used herein to refer to a deficit or impairment in any domain of cognition. Cognitive dysfunction may be a symptom of a patient's underlying condition.

DSM-5 defines six major domains of cognitive function: complex attention, executive functions, learning and memory, language, perceptual-motor functions, and social cognition.

Cognitive impairment can affect one or more of these domains. In fact, cognitive abilities are highly interconnected, and it's common for more than one domain to be affected.

For example, the domain complex attention includes the subdomains sustained attention (commonly called 'focus' or 'concentration'), divided attention, selective attention, and processing speed.

Therefore, complex attention clearly encompasses aspects important for various cognitive tasks, such as executive functions and learning and memory. Cognitive control or executive functions are inherently dependent on attention. Furthermore, cognition and decision-making are significantly influenced by attentional capacity.

Consequently, attention is not only tested in isolation, but also, for example, in cognitive control tasks/executive functions. Impaired attention is likely to impair other cognitive abilities as well. Understanding language, recognizing visual-spatial relationships, remembering information, and solving problems require first attending to stimuli.

The term cognitive impairment refers herein to an acquired condition, thus indicating a decline in a previously acquired level of functioning, and may be associated with a variety of processes.

In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained and even improved over time with age. However, even in the absence of any pathological condition, aging leads to a decline in abilities such as abstract thinking, reasoning, and decision-making. This deterioration is associated with underlying age-related deficits in processing speed, attention, memory, and executive function, which are indicative of cognitive aging.

Regardless of normal aging, cognitive impairment may be associated with mental or neurological disorders or some other medical conditions.

Mental or neurological disorders as discussed herein cause or are associated with cognitive dysfunction.

Furthermore, cognitive dysfunction occurs in disorders that present with symptoms characteristic of a neurocognitive disorder, causing clinically significant distress or impairment in social, occupational, or other important areas of functioning, but that do not meet full criteria for any etiologically related disorder.

Cognitive impairment can manifest itself in the form of neurocognitive disorders.

Mild cognitive impairment (MCI), also known as mild cognitive impairment, is characterized by a mild cognitive decline relative to previous performance levels in one or more cognitive domains. Affected patients remain independent and capable of performing everyday tasks. However, they typically function at a suboptimal level. As they utilize compensatory strategies to maintain independence, everyday tasks become more challenging.

In major neurocognitive disorders, significant cognitive decline is observed in one or more cognitive domains relative to previous performance levels. Cognitive deficits impair independence in daily activities.

Measurement of cognitive impairment

Cognitive impairment can be assessed by questionnaires or neuropsychological assessments.

Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a specific psychiatric or neurological disorder may include items related to cognitive function.

A neuropsychological evaluation is a comprehensive assessment of a person's cognitive, psychological/emotional, and behavioral functions. A core component of a neuropsychological evaluation is the administration of neuropsychological tests to formally assess cognitive function.

The results of these tests are compared to norms appropriate for the patient's age, education level, and cultural background. The tests often use a series of performance-based questions, also known as the Neuropsychological Comprehensive Test.

The abilities tested include language processing, visuospatial processing, attention/concentration, verbal learning and memory, visual learning and memory, executive functions, processing speed, and sensory perception.

Common tests to assess cognitive dysfunction include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Psychiatric Cognitive Impairment Inventory (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

The Montreal Cognitive Assessment (MoCA) is a widely used screening test to detect cognitive impairment. It assesses various cognitive domains: short-term memory; visuospatial abilities; executive function; attention, concentration, and working memory; language; and spatial and temporal orientation. The total possible score is 30; a score of 26 or higher is considered normal; a score of 18-25 indicates mild cognitive impairment; a score of 10-17 indicates moderate cognitive impairment; and a score of less than 10 indicates severe cognitive impairment.

The Mini-Mental State Examination (MMSE) is an 11-question scale that assesses five cognitive domains: orientation, memory registration, attention and calculation, recall, and language. The maximum score is 30. Raw scores may need to be adjusted for educational attainment and age.

To classify the severity of cognitive impairment, this specification uses the following four cut-off levels: 24 to 30 means no cognitive impairment; 19 to 23 means mild cognitive impairment; 10 to 18 means moderate cognitive impairment; and 9 or less means severe cognitive impairment.

The MMSE, which is used repeatedly, is suitable for measuring changes in cognitive status.

The Mini-Cog ^™ is a short cognitive screening questionnaire. It combines three-word recall with a clock drawing test. The clock drawing test assesses several cognitive domains that may be affected, such as executive function, visuospatial abilities, motor control, and attention. One point is awarded for each three words correctly recalled; a correctly drawn clock is worth two points. A score below four points indicates cognitive impairment.

The Screening for Cognitive Impairment in Psychiatry (SCIP) is a well-validated screening tool for assessing cognitive performance in psychiatric patients.

The SCIP consists of five subscales: the Verbal Learning Test - Immediate (VLT-I), the Working Memory Test (WMT), the Verbal Fluency Test (VFT), the Verbal Learning Test - Delayed (VLT-D), and the Processing Speed Test (PST). The three different test forms facilitate test repetition and reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated by summing the subscale scores. A total score below 70 indicates cognitive impairment.

Cognitive impairment can also be assessed using the MATRICS Consensus Cognitive Comprehensive Test (MCCB) or one or more of its various subtests. These subtests include the Trail Making Test, Part A (processing speed test); the Brief Assessment of Cognition in Schizophrenia, Symbol Coding subtest (processing speed); the Hopkins Verbal Learning Test-Revised, Immediate Recall, Three Learning Trials Only (verbal learning); the Wechsler Memory Scale, 3rd Edition, Spatial Span subtest (working memory (nonverbal)); the Letter-Number Span test (working memory (verbal)); the Neuropsychological Assessment Battery, Maze subtest (reasoning and problem solving); and the Brief Visuospatial Memory Test-Revised (visual learning). The tests are the Category Fluency Test, Animal Naming (processing speed); the Mayer-Salovey-Caruso Emotional Intelligence Test, emotion management (social cognition); and the Continuous Performance Test, Identical Pairs version (attention/vigilance).

Comprehensive tests are suitable for measuring cognitive changes.

Additional tests include the Verbal Recognition Memory (VRM) test, the Rapid Visual Information Processing (RVP) test, the Spatial Working Memory (SWM) test, and the Digit Symbol Substitution Test (DSST).

Underlying mechanisms of cognitive dysfunction

Brain processes can be examined using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). Observed patterns that characterize a neural network of brain regions with consistent patterns of signal fluctuations are called resting-state networks (RSNs).

Various resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen primarily in task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks are characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

RSNs have been shown to be responsible for various aspects of complex brain function, and these connected neural networks have been found to be impaired in various disease states. These disease states, including specific forms of cognitive dysfunction, are associated with altered functional connectivity within specific resting-state neural networks and/or between one or more regions within one or more additional resting-state neural networks.

Resting-state fMRI is particularly advantageous when testing populations affected by cognitive impairment because it allows examination of functional connectivity while eliminating the burden of tasks that may be confounded by potential cognitive or motor impairments.

Cognitive processes are reflected by the functional connectivity of specific brain regions within and/or between regions located in different neural networks.

In particular, certain core neural networks, sometimes called 'higher-order cognitive networks', appear to be important for most mental activities.

The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), central executive network (CEN), or executive network (EN), is generally associated with executive functions. These functions include storing and updating relevant information in working memory, inhibiting impulsive responses, and guiding decision-making and goal-directed behavior using flexible problem-solving strategies.

Another key neural network is the default mode network (DMN). The DMN comprises brain regions that are most active when a person's attention is not focused on any specific task. DMN activity is associated with reflection, episodic memory, memory consolidation, social and self-relevant cognition, the integration of cognitive and emotional processing, and free thought resulting from task-unrelated mind wandering.

The third neural network is the salience network, also known as the cingulo-opercular network. This network is involved in identifying salient stimuli and events—those that other brain networks should pay attention to. This network plays a central role in controlling mental processes and behavior.

The fourth neural network is the dorsal attention network (DAN). The DAN is associated with top-down, goal-directed attentional processes.

The neural networks above do not operate independently. In fact, there are many connections between them. Cooperation between neural networks is crucial for task-specific functions.

Throughout life, brain neural networks undergo functional reorganization that simultaneously impacts cognition. In healthy aging, age-related changes are observed in higher-order cognitive neural networks.

Patients with cognitive impairment exhibit altered functional connectivity within and/or between resting-state neural networks compared to healthy, age-matched controls. Alterations are observed within and/or between the default mode network, executive network, salience network, and dorsal attention network.

In many cases, the resting-state neural networks involved in cognition are affected by mental or neurological disorders, as discussed herein.

Resting-state neural networks involved in cognition are also affected by certain medical conditions as well as psychiatric or neurological conditions that result in unspecified neurocognitive disorders.

Furthermore, resting-state neural networks associated with cognition are affected by sleep disorders, such as insomnia. In fact, cognitive dysfunction and sleep disorders are correlated.

Cognitive function is impaired in patients with sleep disorders, and patients with cognitive dysfunction often also suffer from sleep disturbances.

Treatment of cognitive dysfunction

According to the present invention, cognitive impairment occurring in patients suffering from mental or neurological disorders, or medical conditions leading to associated mental or neurological disorders, can be treated. Furthermore, cognitive impairment occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

Cognitive dysfunction in unspecified neurocognitive disorders can be treated similarly.

In patients suffering from cognitive impairment associated with another condition as described in detail above, treatment of cognitive impairment according to the present invention leads to improvement of the condition associated with cognitive impairment.

Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and/or between neural networks at rest. This disruption reestablishes pathologically miswired connections when the neural network reconnects. New, healthy functional connections are established with lasting effects.

Accordingly, according to the present invention, influencing these neural networks by the treatment described herein will improve cognitive dysfunction, and if the patient being treated suffers from a mental or neurological disorder, will also improve that disorder; if the patient being treated suffers from a medical condition leading to an associated mental or neurological condition, will also improve the associated mental or neurological condition; if the patient being treated suffers from a sleep disorder, for example, insomnia, will also improve the sleep disorder, for example, insomnia; and if the patient suffers from an unspecified neurocognitive disorder, will also improve one or more other symptoms of that disorder.

To further support the clinical application of 5-MeO-DMT in patients with cognitive dysfunction, the inventors evaluated clinical data using 5-MeO-DMT in patients being treated for psychiatric disorders and confirmed specific improvements in cognitive dysfunction that were generally observed in patients with other disorders.

The data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). While TRD is a specific condition, the inventors determined that certain clinical observations made in the trial are relevant for designing treatments for other conditions associated with cognitive impairment, as discussed in detail below.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized dosing regimen (IDR) within a day, which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) based on the intensity of the patient-reported hallucinatory experience, were of interest.

The collected data were assessed using the Montgomery-Osberg Depression Rating Scale [Montgomery- The trial included evaluations of treated patients on several scales, including the Multi-Analytic Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on items encompassing various rating scales, noting that specific subscale items, such as those related to cognitive impairment, were associated with other conditions based on similarly altered functional connectivity within and/or between the default state, executive control, salience, and dorsal attention networks.

A significant improvement was observed in a large number of patients within the recruited cohort, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

More specifically, cognitive impairment, particularly attention deficit, can be treated with 5-MeO-DMT. 5-MeO-DMT can be administered to patients to reduce or eliminate cognitive impairment, particularly attention deficit.

The MADRS item that is particularly relevant to impaired concentration and memory is "Difficulty Concentrating." This item indicates difficulty organizing one's thoughts and a lack of concentration that is disabling, and is scored on a scale from 0 to 6. If the patient has no difficulty concentrating, the score is 0. If the patient occasionally has difficulty organizing thoughts, the score is 2. If the patient has difficulty concentrating and sustaining thoughts, resulting in a reduced ability to read or converse, the score is 4. If the patient cannot read or converse without significant difficulty, the score is 6.

In the study group receiving individualized dosing regimens, the aggregate score for the MADRS item 'Diminished Concentration' for all eight patients was 30 at baseline.

After 2 hours, the score decreased to 11 points, representing a 19-point improvement or 63% improvement. On the first day after treatment, the score decreased to 1 point, representing a 29-point improvement or 97% improvement. On the seventh day after treatment, the score decreased to 9 points, representing a 21-point improvement or 70% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'impaired concentration' for all four patients was 16 at baseline.

After 2 hours, the score decreased to 7, representing a 9-point improvement or 56% improvement. On day 1 after treatment, the score decreased to 2, representing a 14-point improvement or 88% improvement. On day 7 after treatment, the score decreased to 3, representing a 13-point improvement or 81% improvement.

Consequently, according to the present invention, treating a patient suffering from cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment.

More particularly, treating a patient with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates cognitive dysfunction, wherein the patient suffers from cognitive dysfunction, wherein the cognitive dysfunction is a deficit or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. For example, the cognitive dysfunction is reduced or eliminated when it affects one or more subdomains of the cognitive domain complex attention, particularly sustained attention, selected from the cognitive domain complex attention, such as sustained attention, divided attention, selective attention, and processing speed.

In patients suffering from cognitive dysfunction associated with a mental or neurological disorder, treatment of cognitive dysfunction according to the present invention results in improvement of the pathology associated with cognitive dysfunction.

While cognitive impairment can be considered a treatable condition independent of any other underlying conditions, disorders, or symptoms an individual may have, several mental and neurological disorders are associated with cognitive impairment. Notably, the relationship between cognitive impairment and mental disorders is bidirectional. Not only can mental disorders negatively impact cognitive function, but cognitive impairment can also be a factor influencing the onset, progression, and prognosis of mental or neurological disorders.

In many cases, the resting-state neural networks involved in cognitive dysfunction are also involved in the conditions listed above.

5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting neural networks. This disruption reestablishes pathologically miswired brain connections as the neural network reconnects. New, healthy functional connections are established with lasting effects.

unrest

Anxiety is sometimes defined as 'a worrisome anticipation of future danger or misfortune, accompanied by physical symptoms of discomfort or tension.'

Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are subjectively perceived as threatening, and is often accompanied by muscle tension, restlessness, fatigue, shortness of breath, abdominal tension, nausea, and problems concentrating.

In anxiety disorders or other anxiety-related mental or neurological disorders, feelings of anxiety are difficult to control and interfere with daily activities.

Anxiety is a core feature of anxiety disorders, including separation anxiety disorder, specific phobias, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance/drug-induced anxiety disorder.

Anxiety is also associated with several other mental and neurological disorders. Anxiety is also associated with sleep disorders.

Measurement of anxiety

Several assessment scales for assessing anxiety are known in the art, and anxiety symptoms are additionally assessed as part of various assessment scales used to assess psychiatric and neurological disorders.

The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. It is administered by clinicians. It consists of 14 items, divided into two groups: psychological items (1-6 and 14), which specifically measure mental agitation and psychological distress, and physical items (7-13), which specifically measure physical ailments associated with anxiety.

The HAM-A items are shown in the table below.

The total score is calculated by summing the 14 items. The total score ranges from 0 to 56. Higher scores indicate greater anxiety.

A score of 7 or less is considered to indicate no or minimal anxiety, 8 to 14 to indicate mild anxiety, 15 to 23 to indicate moderate anxiety, and 24 or more to indicate severe anxiety.

The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on somatic symptoms. Items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (severe: almost unbearable). The total score ranges from 0 to 63.

As used herein, the term subthreshold anxiety means, specifically, that the patient has a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 but less than 18 and/or a Beck Anxiety Inventory (BAI) score of at least 11 but less than 16.

Underlying mechanisms of anxiety

Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). Observed patterns that characterize a neural network of brain regions with consistent patterns of signal fluctuations are called resting-state networks (RSNs).

Various resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen primarily in task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks are characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

The RSN has been demonstrated to be responsible for various aspects of complex brain function, and these neural networks have been shown to be impaired in various disease states. These disease states, including certain forms of anxiety, are associated with altered functional connectivity within specific resting-state neural networks and/or between one or more regions of one or more additional resting-state neural networks.

These studies have shown that many brain regions contribute to anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal connectivity between the amygdala-frontal cortex and the fronto-striatal regions. Anxiety and anxiety disorders are associated with specific alterations in resting-state neural networks.

Anxiety and anxiety disorders exhibit abnormalities within and/or between the default mode, salience, and sensorimotor networks. The resting-state balance within and/or between these networks varies across different anxiety disorders.

Treatment of anxiety

According to the present invention, anxiety can be treated in patients suffering from anxiety disorders, or other mental or nervous system disorders associated with anxiety. Furthermore, anxiety can be treated in patients suffering from sleep disorders, such as insomnia.

In patients suffering from anxiety associated with another mental or nervous disorder or sleep disorder, for example, insomnia, the treatment of anxiety according to the present invention improves the anxiety-associated condition.

Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and/or between neural networks at rest. This disruption reestablishes pathologically miswired connections when the neural network reconnects. New, healthy functional connections are established with lasting effects.

Accordingly, according to the present invention, by influencing the neural network with the therapy as described herein, anxiety will be improved, and if the treated patient suffers from another mental or neurological disorder associated with anxiety, that disorder will also be improved, and if the treated patient suffers from a sleep disorder, for example, insomnia, that sleep disorder, for example, insomnia, will also be improved.

To further support the clinical application of 5-MeO-DMT in patients suffering from anxiety, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in anxiety that were typically also observed in patients with other disorders.

These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with Treatment-Resistant Depression (TRD) (see also the Examples section below). While TRD is a specific condition, the inventors have determined that certain clinical observations made in the trial are relevant for designing treatments for anxiety disorders and other anxiety-related conditions, as discussed in detail below.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized daily dosing regimen (IDR), which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) within a day based on the intensity of the patient's reported hallucinatory experience, were of interest.

The collected data included patient assessments of treatment on several scales, including the Montgomery-Osberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the trial focused on demonstrating treatment efficacy through improvements in overall MADRS scores, the inventors focused on items encompassing various rating scales and noted that specific subscale items, such as anxiety-related items, were also relevant for other conditions based on similarly altered functional connectivity within and/or between resting-state neural networks.

A significant improvement was observed in a large number of patients within the recruited cohort, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

More specifically, anxiety is a condition that can be treated with 5-MeO-DMT. Administering 5-MeO-DMT to a patient can reduce or eliminate anxiety in that patient.

In this context, a particularly relevant BPRS item is "Anxiety." This item relates to reported feelings of worry, tension, fear, panic, or worry. Possible scores are as follows:

1 - No anxiety.

2 - Very mild. Most normal people report some discomfort due to worries that occur more frequently than usual or are rare.

3 - Mild. Frequently anxious, but easily distracted by other things.

4 - Moderate. Mostly anxious and easily distracted, but no functional impairment, or occasionally anxious with autonomic nervous system involvement, but no functional impairment.

5 - Moderately severe. Frequent but not daily periods of anxiety accompanied by autonomic dysfunction, or some areas of functioning are disrupted by anxiety or worry.

6 - Severe. Anxiety accompanied by autonomic dysfunction is present daily, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or constant worry.

7 - Extremely severe. Anxiety accompanied by autonomic dysfunction persists throughout the day, or most areas of functioning are disrupted by anxiety or constant worry.

In the study group receiving individualized dosing regimens, the aggregate score for the BPRS item 'Anxiety' across all eight patients was 37 at baseline.

After 3 hours, the score decreased to 19 points, corresponding to an 18-point or 49% improvement. On day 1 after treatment, the score decreased to 16 points, corresponding to an 21-point or 57% improvement. On day 7 after treatment, the score decreased to 17 points, corresponding to an 20-point or 54% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Anxiety' across all four patients was 25 at baseline.

After 3 hours, the score decreased to 11 points, corresponding to a 14-point or 56% improvement. On the first day after treatment, the score decreased to 6 points, corresponding to a 19-point or 76% improvement. On the seventh day after treatment, the score decreased to 6 points, corresponding to a 19-point or 76% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat anxiety in patients, such as patients suffering from anxiety disorders and patients suffering from psychiatric or neurological disorders with associated anxiety.

Consequently, according to the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

The MADRS item " Inner Tension " describes feelings of mental tension that surge with undefined discomfort, irritability, inner turmoil, panic, fear, or distress. This is rated according to intensity, frequency, duration, and the degree of reassurance needed.

If the patient is calm and experiences only brief periods of internal tension, a score of 0 is assigned. If the patient experiences occasional feelings of anxiety or vague discomfort, a score of 2 is assigned. If the patient experiences persistent internal tension or intermittent panic that can be overcome with some difficulty, a score of 4 is assigned. If the patient experiences persistent fear or distress, or extreme panic, a score of 6 is assigned.

In the study indicated above involving patients with TRD, the aggregate score for the MADRS item 'Internal Tension' across all eight patients in the study group receiving the individualized dosing regimen was 26 at baseline. Two hours later, this score decreased to 11 points, corresponding to a 15-point or 58% improvement. On day 1, this score decreased to 6 points, corresponding to a 20-point or 77% improvement. On day 7, this score decreased to 12 points, corresponding to a 14-point or 54% improvement.

The aggregated MADRS score for the "Inner Tension" item for all four patients in the 12 mg group was 13 at baseline. Two hours later, it decreased to 2, corresponding to an 11-point or 85% improvement. On day 1, it decreased to 3, corresponding to a 10-point or 77% improvement. On day 7, it decreased to 5, corresponding to an 8-point or 62% improvement.

These results further support the inventors' conclusion that the treatment according to the present invention reduces or eliminates symptoms of anxiety.

Treatment according to the present invention results in a clinical response in a patient suffering from anxiety symptoms, as reflected by a decrease in HAM-A score of at least 50% compared to the pre-treatment score, respectively, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., at about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and/or at day 28.

A clinical response in a patient suffering from anxiety symptoms, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response in a patient suffering from anxiety symptoms, as reflected by a decrease in the HAM-A score of at least 50%, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from anxiety symptoms, relief of anxiety symptoms is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, relief of anxiety symptoms occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, relief of anxiety symptoms preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Consequently, according to the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

psychomotor retardation

The main features observed in patients suffering from psychomotor delay are decreased energy and activity, and decreased motivation.

Psychomotor retardation involves a slowing of an individual's thinking and a reduction in physical movement. Psychomotor impairment can cause a noticeable slowing of physical and emotional responses.

Psychomotor delay may be associated with mental or neurological disorders or some other medical conditions.

Mental or neurological disorders that lead to or are associated with psychomotor retardation include disorders characterized by depressive episodes, such as major depressive disorder [MDD]; bipolar disorders [BD], such as bipolar I disorder and bipolar II disorder; postpartum depression [PPD]; seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

Psychomotor retardation may also occur in patients with sleep disorders, such as insomnia.

Measurement of psychomotor delay

Psychomotor delay can be assessed using a variety of measures. These may include, for example, various drawing tasks and tests, such as the Trail Making Test (TMT), the Digit Symbol Substitution Test (DSST), the Gibson Spiral Maze Test (GSM), and other tests known to those skilled in the art.

For example, in the Trail Making Test (TMT), subjects must connect 25 circles containing either numbers (TMT A) or combinations of numbers and letters (TMT B) in ascending order. The task requirements for TMT-B are similar, except that subjects must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C). Thus, this test assesses processing speed (TMT A) or cognitive flexibility (TMT B). Scores for each section represent the time required to complete the task.

Another test that incorporates graphomotor abilities is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is unaffected by cognitive abilities. Subjects completing the GSM must correctly navigate a spiral maze from the start to the end without touching the boundary line.

The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of digit-symbol pairs followed by a sequence of digits. Under each digit, the subject must write down the corresponding symbol as quickly as possible. Scoring is based on the number of symbols correctly reported within 90 seconds. Another example of a motor test is the finger tapping test.

Thus, certain tests combine measures of both motor and cognitive aspects of psychomotor retardation, whereas other tests assess only the motor aspect.

Analysis of language may be an additional indicator of psychomotor delay.

The main scales that can be assessed and measured are the severity of psychomotor delay, the Salpêtrière retardation grading scale ( These include the Retardation Rating Scale (SRRS) and the Motor Agitation and Retardation Scale (MARS).

The Salpêtrière Retardation Rating Scale (SRRS), developed by the American Psychological Association, assesses cognitive and motor aspects using 15 items. The first three items measure movement, specifically the quality of gait and slowness of limb, trunk, head, and neck movements. The next three items focus on language skills, including speech flow, tone of voice, and length of responses. Two items are designed to objectively measure cognitive function. These questions are based on interview conversations and measure the patient's ability to access and expand on topics. Additional items are subjective and assess rumination, fatigue, attention level, time perception, memory, and concentration. The final item of the scale provides a global assessment of the patient's psychomotor retardation. Items are rated based on the severity of the presented symptoms, from 0 (no symptoms) to 4 (severe symptoms), resulting in a total score ranging from 0 to 60.

The Motor Agitation and Retardation Scale (MARS) assesses only motor aspects. It is designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five major somatic categories: eyes, face, voice, limbs, and trunk, and the scale contains 19 items. The eye category includes items on gaze direction, blink rate, gaze, and eye movements. Items related to the face category include facial expression and expressiveness. The voice category includes items on volume, stuttering, timbre, and onset time. Items under the limb category include hand, foot, and leg movements, gait, slowness of movement, and hand tension. Items under the trunk category include posture, immobility, and pivoting. Each item is rated on a severity scale from 1 to 4, with 4 being the most severe. Nine of the 19 items are related to motor agitation, and 10 items assess motor retardation. Delayed items include abnormal gait, immobility of the trunk/proximal limbs, postural collapse, and slowness of movement (i.e., limb and trunk categories); lack of facial expressiveness and downcast gaze (i.e., eyes and face categories); and decreased vocal loudness, stuttering, delayed initiation of speech, and monotony (i.e., voice categories). The MARS scale provides a rapid clinical assessment of motor signs.

Resting-state neural networks and psychomotor delay

Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). Observed patterns that characterize a neural network of brain regions with consistent patterns of signal fluctuations are called resting-state networks (RSNs).

Various resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen primarily in task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

The RSN has been shown to be responsible for various aspects of complex brain function, and this connectivity network has been found to be impaired in various disease states. These disease states, including specific forms of psychomotor delay, are associated with altered functional connectivity within specific resting-state neural networks and/or between one or more regions of one or more additional resting-state neural networks.

For example, abnormal functional connectivity from the somatosensory motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks has been reported, which has been correlated with both psychomotor retardation and agitation in depressive disorders.

In many cases, the resting-state neural networks involved in psychomotor retardation are affected by mental or neurological disorders characterized by depressive episodes, such as major depressive disorder [MDD]; bipolar disorders [BD], such as bipolar I disorder and bipolar II disorder; postpartum depression [PPD]; seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

The resting-state neural networks involved in psychomotor retardation are also affected by sleep disorders, such as insomnia. Indeed, psychomotor retardation and sleep disturbances are correlated.

Treatment of psychomotor retardation and mental or neurological disorders

According to the present invention, psychomotor retardation can be treated in patients suffering from mental or neurological disorders. Furthermore, psychomotor retardation occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

In patients suffering from psychomotor delay associated with other conditions as detailed above, the treatment of psychomotor delay according to the present invention results in improvement of the conditions associated with psychomotor delay.

Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and/or between neural networks at rest. This disruption reestablishes pathologically miswired connections when the neural network reconnects. New, healthy functional connections are established with lasting effects.

Accordingly, according to the present invention, influencing these resting state neural networks by the therapy described herein will result in an improvement in psychomotor retardation, and if the treated patient suffers from a psychiatric or neurological disorder, it will also result in an improvement in that disorder; and if the treated patient suffers from a sleep disorder, for example, insomnia, it will also result in an improvement in the sleep disorder, for example, insomnia.

To further support the clinical application of 5-MeO-DMT in patients suffering from psychomotor delay, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in psychomotor delay that were typically also observed in patients with other disorders.

These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). While TRD is a unique condition, the inventors have identified specific clinical observations from the trial as relevant for designing treatments for other conditions associated with psychomotor retardation, as discussed in detail below.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized daily dosing regimen (IDR), which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) within a day based on the intensity of the patient's reported hallucinatory experience, are of interest.

The collected data included assessments of treated patients on several scales, including the Montgomery-Osberg Depression Rating Scale (MADRS). While the focus of this trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on items encompassing various rating scales, noting that specific subscale items, such as those related to psychomotor retardation, have been linked to other conditions based on similarly altered functional connectivity within and/or between the motor/sensorimotor, visual, dorsal attention, and default mode networks.

A significant improvement was observed in a large number of patients within the recruited cohort, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

More specifically, a condition that can be treated by administration of 5-MeO-DMT is psychomotor retardation. Administration of 5-MeO-DMT to a patient can reduce or eliminate psychomotor retardation in said patient.

The MADRS scale item that is particularly relevant to psychomotor retardation is 'boredom', which refers to difficulty initiating daily activities or slowness in initiating and carrying them out.

A score of 0 indicates that the patient has little or no difficulty in starting activities and is not slow. If the patient has difficulty initiating activities, a score of 2 is given. A score of 4 indicates that the patient has difficulty initiating simple daily activities that require effort. A score of 6 indicates complete ennui, where the patient is unable to do anything without assistance.

In the study group receiving individualized dosing regimens, the aggregate score for the MADRS item 'Boring' across all eight patients was 27 at baseline.

After 2 hours, this had decreased to 10, corresponding to a 17-point or 63% improvement. On the first day after treatment, this had decreased to 5, corresponding to a 22-point or 81% improvement. On the seventh day after treatment, this had decreased to 3, corresponding to a 24-point or 89% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Malaise' was 16 at baseline across all four patients. Two hours later, this had decreased to 10, corresponding to a 6-point or 38% improvement. On day 1 post-treatment, this had decreased to 0, corresponding to a 16-point or 100% improvement. On day 7 post-treatment, this had decreased to 3, corresponding to a 13-point or 81% improvement.

Therefore, scores on the "boredom" scale, a scale item particularly associated with psychomotor retardation, were significantly improved. The present inventors concluded that 5-MeO-DMT can be used to treat psychomotor retardation in patients, particularly those suffering from psychiatric or neurological disorders or sleep disorders such as insomnia.

Consequently, according to the present invention, treating a patient suffering from psychomotor retardation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates psychomotor retardation.

social/emotional withdrawal or isolation

Symptoms such as anhedonia, emotional withdrawal, and affective blunting are collectively grouped together in this specification as social/emotional withdrawal or detachment. Reduced social participation is an additional aspect associated with social/emotional withdrawal or detachment.

Anhedonia is the inability to experience pleasure. A patient does not have anhedonia unless they subjectively experience a decrease in their ability to experience pleasure in everyday life. Anhedonia is classified as mild (slightly reduced pleasure in normally enjoyable activities), moderate (significantly reduced pleasure in normally enjoyable activities or some pleasure maintained in reduced activities), or severe (completely incapable of experiencing pleasure).

Anhedonia includes consumptive (or liking) and anticipatory (or wanting) components. Consumptive pleasure refers to the "momentary" pleasure experienced through direct participation in a pleasurable activity, while anticipatory pleasure refers to the experience of pleasure associated with a future activity.

Affective blunting is characterized by a subjective sense of diminished intensity or range of emotions or affect. Affective blunting does not occur if a subject lacks a sense of diminished intensity or range of emotions or affect. It is mild, with slight limitations in affect range or intensity or a temporary reduction in affect range or intensity; moderate, with significant limitations in affect range or intensity, with preservation of some emotions (e.g., an inability to cry); and severe, with marked and pervasive limitations in affect range or an inability to experience general emotions.

Emotional withdrawal or detachment is the inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item related to emotional withdrawal, which is characterized by a lack of emotional engagement during the interview. According to the description of this BPRS item, if a subject interacts with the interviewer naturally most of the time, although there is some emotional engagement, as evidenced by occasional reluctance to offer input, occasional preoccupation, or unnatural smiling, there is no emotional withdrawal. If a subject lacks emotional engagement, as evidenced by a noticeable lack of input, preoccupation, or warmth, but responds when approached by the interviewer, there is a mild form of emotional withdrawal. This is moderate if the subject is not attentive, avoids eye contact, appears unconcerned with the interviewer's listening, or is preoccupied with psychotic material, making little emotional contact during the interview. This is also moderately severe if the subject lacks emotional engagement during most of the interview. A severe form exists if the subject actively avoids emotional engagement, or if the subject frequently responds inattentively, responds with "yes/no" responses, or responds with minimal affect. This is extremely severe if the subject persistently avoids emotional engagement, is unresponsive, responds with a 'yes/no' response, walks away during the interview, or refuses to respond at all.

Reduced social participation is characterized by subjective reports of decreased social and interpersonal participation or interaction. If there are no reports of decreased social and interpersonal participation or interaction, there is no reduced social participation. This is classified as mild if there is a slight decrease in social participation without impairment in social or interpersonal functioning; moderate if there is a clear decrease in social participation with some functional consequences, such as avoidance of some social participation or conversation; and severe if there is a marked decrease in social interaction or avoidance of almost all forms of social contact, such as refusing to answer the phone or see friends or family.

Social/emotional withdrawal or detachment may be associated with mental or neurological disorders or some other medical conditions.

Mental or neurological disorders that lead to or are associated with social/emotional withdrawal or detachment, including disorders characterized by depressive episodes, such as major depressive disorder [MDD], bipolar disorders [BD], such as bipolar I disorder and bipolar II disorder, postpartum depression [PPD], seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder [GAD] and social anxiety disorder [SAD]; obsessive-compulsive and related disorders, such as obsessive-compulsive disorder [OCD] and body dysmorphic disorder [BDD]; posttraumatic stress disorder [PTSD]; pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia [AD]; dementia with Lewy bodies [DLB]; vascular dementia and frontotemporal dementia [FTD]; Parkinson's disease (PD); eating disorders; Autism spectrum disorder [ASD]; attention deficit hyperactivity disorder [ADHD]; and personality disorders, such as schizotypal personality disorder and borderline personality disorder [BPD].

Social/emotional withdrawal or detachment may also occur in patients suffering from sleep disorders, such as insomnia.

Social/emotional withdrawal or detachment may also occur in patients with medical conditions that lead to associated psychiatric or neurological conditions, including traumatic brain injury (TBI).

Measurement of social/emotional withdrawal or isolation

Social/emotional withdrawal or isolation (often referred to herein as social/emotional withdrawal) or its individual aspects, such as anhedonia, emotional withdrawal and emotional blunting, can be assessed by different instruments, such as questionnaires or scales.

Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a specific mental or neurological disorder may include items related to social/emotional withdrawal or isolation.

The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, or the inability to experience pleasure. The items cover the domains of social interaction, food and drink, sensory experiences, and interest/pleasure. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or higher. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Any "disagree" response is scored 1, and any "agree" response is scored 0. The final score ranges from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. While the SHAPS was initially used to measure anhedonia in depression, it is also frequently used to assess anhedonia in other patient groups.

The SHAPS measures pleasant tone over the past few days, using 14 hypothetical items. However, due to the hypothetical nature of the items, a shorter recall period may be appropriate for early assessment.

Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS) can be used to assess anhedonia, measuring interest, motivation, effort, and consumptive pleasure across four domains: hobbies, food/drink, social activities, and sensory experiences. It consists of 17 items assessing current anhedonia status. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (extremely so), with higher values indicating less anhedonia. All items are summed to a total score ranging from 0 to 68. For each of the four pleasure domains: hobbies (4 items, total score 0 to 16), food/drink (4 items, total score 0 to 16), social activities (4 items, total score 0 to 16), and sensory experiences (5 items, total score 0 to 20), participants are asked to provide two to three of their favorite examples.

The Personality Inventory for DSM-5 (PID-5) - Adult is a 220-item self-assessment personality trait assessment scale for adults 18 years of age and older. It assesses 25 personality trait aspects, including anhedonia, anxiety, attention seeking, callousness, manipulativeness, depressiveness, distractibility, eccentricity, emotional instability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, manipulativeness, perceptual dysregulation, perseveration, restricted affect, rigid perfectionism, risk taking, separation anxiety, compliance, suspiciousness, unusual beliefs and experiences, and withdrawal, with each trait aspect consisting of 4 to 14 items.

Trait pattern Anhedonia contains items 1, 23, 26, 30R, 124, 155R, 157, 189 (reverse-scored items are indicated by the letter 'R'), trait pattern Withdrawal contains items 10, 20, 75, 82, 136, 146, 147, 161, 182, 186, and trait pattern Intimacy Avoidance contains items 89, 97R, 108, 120, 145, 203. These three trait patterns can be combined to create broader trait domains designated as separate.

Before visiting a clinician, subjects complete a scale. Each item asks subjects to rate how well it describes them in general.

Each item on the scale is rated on a 4-point scale. Response categories for items are 0 = very false or often false, 1 = sometimes or somewhat false, 2 = sometimes or somewhat true, and 3 = very true or often true. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, the items were reverse-coded before calculating scale scores.

The scores for each trait facet should be summed and entered into the appropriate raw facet score box. Clinicians are also asked to calculate and use a mean score for each facet and domain. The mean score reduces the overall score as well as each domain score to a 4-point scale, allowing the clinician to consider the individual's personality dysfunction relative to observed norms. The mean facet score is calculated by dividing the raw facet score by the number of items in the facet (for example, if all items within the "Anhedonia" facet were rated "Sometimes or Somewhat True," the mean facet score would be 16/8 = 2, indicating moderate anhedonia). The mean domain score is calculated by summing and then averaging the scores of three facets that primarily contribute to a particular domain. For example, if the mean facet scores for Anhedonia, Intimacy Avoidance, and Withdrawal (a scale primarily indexing Detachment) are all 2, then the sum of these scores would be 6, and the mean domain score would be 6/3 = 2. A higher mean score indicates greater dysfunction in a particular personality trait facet or domain.

High scores on a dimension or domain may indicate significant and problematic areas for the individual receiving care that may require further evaluation, treatment, and follow-up.

Resting neural networks and social/emotional withdrawal or isolation

Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). The observed patterns that characterize a network of brain regions with consistent patterns of signal changes are called resting-state neural networks (RSNs).

Different resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen in most task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks are characterized for attention, memory, cognitive control, default mode, motor, and sensory systems.

The RSN has been shown to be responsible for various aspects of complex brain function, and this network of connections has been found to be impaired in a variety of disease states. These disease states, including certain forms of social/emotional withdrawal or detachment, are associated with altered functional connectivity between one or more regions within a specific resting-state neural network and/or within one or more additional resting-state neural networks.

Alterations in the RSN are also associated with anhedonia, a core aspect of social/emotional withdrawal or detachment. More specifically, anhedonia is associated with visual network hyperconnectivity and expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia is also associated with decreased connectivity among the DMN, salience, DAN, somatomotor, and visual networks.

Furthermore, emotional dissociation in adult psychopathy is associated with structural abnormalities in the dorsal DMN. The dorsal DMN is of particular interest in the pathogenesis of psychopathy due to its associated functions. Specifically, the dorsal DMN and its associated regions (medial prefrontal cortex and posterior cingulate cortex (PCC)) support affective, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are associated with affective and interpersonal differences that define the disorder.

Thus, patients with social/emotional withdrawal or detachment demonstrate altered functional connectivity within and/or between RSNs compared to healthy age-matched controls. Alterations are observed within and/or between the DMN, salience, DAN, somatomotor, and visual neural networks.

In many cases, RSNs involved in social/emotional withdrawal or detachment are associated with disorders characterized by depressive episodes, such as major depressive disorder [MDD], bipolar disorders [BD], such as bipolar I and II disorders, postpartum depression [PPD], seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder [GAD] and social anxiety disorder [SAD]; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder [OCD] and body dysmorphic disorder [BDD]; posttraumatic stress disorder [PTSD]; pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementias, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies [DLB]; vascular dementia and frontotemporal dementia [FTD]; Parkinson's disease [PD]; eating disorders; autism spectrum disorder [ASD]; Affected by mental or neurological disorders such as attention deficit hyperactivity disorder [ADHD]; and personality disorders, such as schizotypal personality disorder and borderline personality disorder [BPD].

Resting-state neural networks involved in social/emotional withdrawal or detachment are also affected by psychiatric or neurological conditions resulting from certain medical conditions, such as traumatic brain injury (TBI).

The resting-state neural networks involved in social/emotional withdrawal or detachment are also affected by sleep disorders, such as insomnia. Indeed, there is a correlation between social/emotional withdrawal or detachment and sleep disorders.

Treatment of social/emotional withdrawal or isolation and mental or nervous system disorders

According to the present invention, social/emotional withdrawal or isolation can be treated in patients suffering from mental or neurological disorders. Furthermore, social/emotional withdrawal or isolation can be treated in patients suffering from sleep disorders, such as insomnia.

In patients suffering from social/emotional withdrawal or detachment in association with another condition as described in detail above, the treatment of social/emotional withdrawal or detachment according to the present invention improves the condition associated with social/emotional withdrawal or detachment.

Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and/or between neural networks at rest. This disruption reestablishes pathologically miswired connections when the neural network reconnects. New, healthy functional connections are established with lasting effects.

Accordingly, according to the present invention, influencing this neural network by a treatment as described herein will improve social/emotional withdrawal or detachment, and if the treated patient suffers from a mental or neurological disorder, will also improve that disorder, and if the treated patient suffers from a sleep disorder, e.g., insomnia, will also improve the sleep disorder, e.g., insomnia.

To further support the clinical application of 5-MeO-DMT in patients suffering from social/emotional withdrawal or detachment, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in social/emotional withdrawal or detachment commonly observed in patients with other disorders.

These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with Treatment-Resistant Depression (TRD; see also the Examples section below). While TRD is a specific disorder, as discussed in detail below, the inventors believe that certain clinical observations from the trial may be relevant for designing treatments for other conditions associated with social/emotional withdrawal or detachment.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized daily dosing regimen (IDR), which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) within a day based on the intensity of the patient's reported hallucinatory experience, were of interest.

The collected data included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in the overall MADRS score, the inventors focused on items encompassing various rating scales and found that specific subscales, such as those related to social/emotional withdrawal or detachment, were associated with other conditions based on similarly altered functional connectivity within and/or between the default mode neural network, salience, dorsal attention, somatomotor, and visual neural networks.

A significant improvement was observed in a large number of patients within the recruited cohort, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

More specifically, aspects that can be treated by 5-MeO-DMT administration include social/emotional withdrawal or detachment, particularly apnea, emotional withdrawal, and/or affective blunting. An additional aspect of treatment is decreased social participation. Administering 5-MeO-DMT to a patient can reduce or eliminate social/emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and/or affective blunting. Furthermore, decreased social participation is improved, reduced, or eliminated.

The MADRS scale item "Not Feeling," which is specifically related to social/emotional withdrawal or detachment, indicates a subjective experience of decreased interest in one's surroundings or engaging in activities that are typically pleasurable. This reflects a decreased ability to respond emotionally appropriately to situations or people.

A score of 0 indicates normal interest in one's surroundings, while a score of 2 indicates a decreased ability to enjoy usual interests. A score of 4 indicates a loss of interest in one's surroundings and a loss of feelings for friends and acquaintances. A score of 6 reflects emotional numbness, an inability to feel anger, sadness, or joy, and a complete or even painful absence of feelings for close family and friends.

In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item 'Anesthesia' across all eight patients was 36 at baseline. Two hours later, this had decreased to 12 points, representing a 24-point or 67% improvement. On day 1 post-treatment, this had decreased to 2 points, representing a 34-point or 94% improvement. On day 7 post-treatment, this had decreased to 6 points, representing a 30-point or 83% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Anesthesia' across all four patients was 16 at baseline. Two hours later, this had decreased to 9, representing a 7-point or 44% improvement. On day 1 post-treatment, this had decreased to 1, representing a 15-point or 94% improvement. On day 7 post-treatment, this had decreased to 1, representing a 15-point or 94% improvement.

BPRS scale items particularly associated with social/emotional withdrawal or isolation are ‘ emotional withdrawal ’ and ‘ blunted affect ’.

The BPRS item "Emotional Withdrawal" relates to the patient's inability to engage emotionally during the interview. Possible scores are:

1 - No emotional withdrawal.

2 - Very mild. Lacks emotional engagement, sometimes not offering feedback, sometimes appearing preoccupied, or laughing awkwardly, but most of the time, the interviewer interacts spontaneously.

3 - Mild. Lacks emotional engagement, appears visibly absent from the conversation, appears preoccupied, or lacks warmth, but responds when approached by the interviewer.

4 - Moderate. There is little emotional connection during the interview, as the subject may not respond in detail, fail to make eye contact, appear unconcerned with the interviewer, or become preoccupied with psychotic material.

5 - Moderately severe. Same as '4', but there is no emotional contact for most of the interview.

6 - Severe. Actively avoids emotional involvement. Frequently responds infrequently or with yes/no answers (not simply due to persecutory delusions). Responds only with minimal impact.

7 - Extremely severe. Persistently avoids emotional engagement. Does not respond or gives yes/no answers (not simply due to persecutory delusions). Leaves the interview or does not respond at all.

The aggregate score for the BPRS item "Emotional Alienation" was 13 at baseline. Three hours later, it decreased to 8, representing a 5-point or 38% improvement. On day 1 post-treatment, it decreased to 8, representing a 5-point or 38% improvement. On day 7 post-treatment, it decreased to 8, representing a 5-point or 38% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Emotional Withdrawal' was 13 at baseline. After 3 hours, this had decreased to 11, representing a 2-point or 15% improvement. On day 1 post-treatment, this had decreased to 8, representing a 5-point or 38% improvement. On day 7 post-treatment, this had decreased to 6, representing a 7-point or 54% improvement.

The BPRS item "Blunt Affect" is associated with a limited range of emotional expression in the face, voice, and gestures, as well as marked indifference or flatness when discussing painful topics. Possible scores are:

1 - No dulled emotions.

2 - Very mild. Emotions are slightly subdued or reserved, but appropriate facial expressions and vocal tones are within normal limits.

3 - Mild. Overall emotional range is reduced, subdued, or reserved, with few spontaneous and appropriate emotional responses. The tone of voice is somewhat monotonous.

4 - Moderate. The emotional range is markedly reduced, and the patient rarely expresses emotion, laughs, or responds to painful topics. The tone of voice is monotonous, and spontaneous movements are markedly reduced. After the emotion or gesture is expressed, the patient usually returns to a blunted affect.

5 - Moderately severe. The emotional range is greatly reduced, and the patient rarely expresses emotion, laughs, or responds to painful topics except for a few minimal gestures. Facial expressions are infrequently altered. The voice tone is often monotonous.

6 - Severe. There is little emotional range or expression. Speech and gestures are often mechanical. Facial expressions are unchanging. Voice tone is often monotonous.

7 - Extremely severe. There is little emotional range or expressiveness, and movements are stiff. The voice tone is always monotonous.

The aggregate score for the BPRS item "Blunt Affect" was 15 at baseline. Three hours later, this had decreased to 11, representing a 4-point or 27% improvement. On day 1 post-treatment, this had decreased to 8, representing a 7-point or 47% improvement. On day 7 post-treatment, this had decreased to 8, representing a 7-point or 47% improvement.

In the 12 mg group, the aggregate score for the BPRS item "Blunt Affect" was 11 points at baseline. Three hours later, this had decreased to 8 points, representing a 3-point or 27% improvement. On day 1 post-treatment, this had decreased to 6 points, representing a 5-point or 45% improvement. On day 7 post-treatment, this had decreased to 5 points, representing a 6-point or 55% improvement.

Thus, scores on scale items specifically related to social/emotional withdrawal or detachment, namely 'not feeling' (MADRS), 'emotional withdrawal' (BPRS), and 'blunted affect' (BPRS), are significantly improved. The present inventors conclude that 5-MeO-DMT can be used to treat social/emotional withdrawal or detachment in patients, particularly those who also suffer from psychiatric or neurological disorders or sleep disorders, such as insomnia.

Consequently, according to the present invention, treating a patient suffering from social/emotional withdrawal or isolation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social/emotional withdrawal or isolation.

negative thinking

Symptoms such as pessimism, feelings of worthlessness, helplessness and hopelessness, and feelings of pathological, excessive or inappropriate guilt are clustered together here as negative thinking.

Feelings of helplessness and hopelessness (also referred to simply as helplessness and hopelessness) are characterized by a subjective sense of pessimism or depression about the future, and a sense of inability to cope or a loss of control. If a patient does not have these feelings, helplessness and hopelessness are absent. Helplessness and hopelessness are mild, with occasional mild feelings of inability to cope or pessimism; moderate, with frequent feelings of inability to cope or significant feelings of helplessness or hopelessness that occasionally resolve; or severe, with marked and persistent feelings of pessimism, helplessness, or hopelessness.

Feelings of worthlessness (also referred to simply as worthlessness) are characterized by a subjective sense or idea of diminished self-worth or self-esteem. If a patient does not have these feelings, they do not have worthlessness. They may be mild, that is , a slight decrease in self-esteem; moderate, that is , some feelings of worthlessness and diminished self-esteem; or severe, that is , a marked, pervasive, or persistent feeling of worthlessness, such as feeling that others are better off without them and being unable to recognize positive attributes.

Feelings of guilt (also referred to simply as guilt) are characterized by a subjective sense of self-reproach, failure, or regret for past mistakes, real or imagined. If the patient does not experience these feelings, guilt is absent. These may be mild, with a slight decrease in self-esteem or increased self-criticism; moderate, with significant thoughts of failure, self-criticism, inability to cope, or rumination about past failures and their impact on others; or may be perceived as excessive; severe, with marked, pervasive, or persistent guilt, e.g. , feelings of deserving of punishment; or not clearly perceived as excessive.

Negative thinking may be associated with mental or neurological disorders or some other medical conditions.

Mental or neurological disorders that lead to or are associated with negative thinking include disorders characterized by depressive episodes, such as major depressive disorder [MDD], bipolar disorders [BD], such as bipolar I disorder and bipolar II disorder, postpartum depression [PPD], seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder [GAD] and social anxiety disorder [SAD]; obsessive-compulsive and related disorders, such as obsessive-compulsive disorder [OCD] and body dysmorphic disorder [BDD]; posttraumatic stress disorder [PTSD]; pain disorders, such as chronic pain; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementias, such as Alzheimer's dementia (AD); eating disorders; attention-deficit/hyperactivity disorder [ADHD]; and personality disorders, such as schizotypal personality disorder and borderline personality disorder [BPD].

Negative thinking can also occur in patients suffering from sleep disorders, such as insomnia.

Negative thinking may also occur in patients with medical conditions that lead to associated mental or neurological conditions, including traumatic brain injury (TBI).

Measurement of negative thinking

Negative thoughts or their individual aspects, such as feelings of worthlessness, helplessness and hopelessness, and guilt, can be assessed by different instruments, such as questionnaires or scales.

Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a specific mental or neurological disorder may include items related to negative thinking.

Tools that assess relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule-Expanded Form (PANAS-X), or the State Hope Scale [SHS].

The State Shame and Guilt Scale (SSGS) is a self-rating measure of momentary (state) feelings of shame and guilt. It consists of two subscales: Shame and Guilt. The Shame subscale includes items 1, 3, 5, 7, and 9. The Guilt subscale includes items 2, 4, 6, 8, and 10. All items are positively scored and rated on a 5-point Likert scale. It includes statements that the patient can or cannot describe how they are feeling at the moment. Higher scores indicate more intense feelings of shame or guilt.

The Positive and Negative Affect Schedule-Expanded Form (PANAS-X) is an expanded version of the 60-item PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, cheerfulness, self-assurance, alertness, and calmness. Thus, the PANAS-X provides a mood measure at two different levels. The basic negative affect scales are fear, hostility, guilt, and sadness, and the guilt scale includes six items: guilt, shame, blameworthiness, anger with self, self-disgust, and dissatisfaction with self. Each response should be scored as 1 = very little or not at all; 2 = a little; 3 = moderately; 4 = quite a lot; or 5 = extremely. However, investigators facing more severe time constraints may choose to assess only the scales most relevant to their investigation.

More intense feelings of guilt are reflected by higher scores on the guilt scale.

The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item schedule in less than 10 minutes. The scale consists of a number of words and phrases describing different feelings and emotions. Although patients are asked to indicate the extent to which they have felt this way over the past several weeks, trait scores on the PANAS-X scale have been shown to be stable over time, including during the "present moment," "today," and "the past few days," suggesting that shorter recall periods can be used as appropriate.

The State Hope Scale (SHS) has three agency and three pathway items that respondents self-report about how they feel "right now." The agency subscale score is derived by summing items 2, 4, and 6, which relate to the respondents' perceived ability to use their pathways to reach desired goals; the pathway subscale score is derived by adding items 1, 3, and 5, which relate to the thinking used to identify possible ways to achieve goals. The total State Hope Scale score is derived by summing the three agency and three pathway items. Scores can range from a low of 6 to a high of 48, with higher scores on this scale reflecting greater hope.

Negative thinking or aspects thereof are also reflected in other scales such as the HAM-D, MADRS, BPRS or BDRS, where relevant items may be commonly applicable to assessing negative thinking or aspects thereof.

Resting-state neural networks and negative thinking

Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of these spontaneous signals reveals distributed regions with correlated and anticorrelated fluctuations.

In this way, resting-state fMRI can be used to characterize large-scale functional neural networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., during rest). The observed patterns that characterize a network of brain regions with consistent patterns of signal changes are called resting-state neural networks (RSNs).

Different resting-state neural networks have been identified and named based on spatial similarities between resting-state neural networks and activation patterns seen in most task fMRI experiments.

Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state neural networks are characterized for attention, memory, cognitive control, default mode, motor, and sensory systems.

The RSN has been shown to be responsible for various aspects of complex brain function, and this connectivity network has been found to be impaired in various disease states. These disease states, which involve specific forms of negative thinking, are associated with altered functional connectivity within specific resting-state neural networks and/or between one or more regions of one or more additional resting-state neural networks.

Major depressive disorder (MDD) is a disorder characterized by high levels of widespread negative affect and low levels of positive affect. More specifically, decreased levels of positive affect, such as hope, are associated with increased levels of hopelessness and increased levels of negative affect, such as guilt. MDD has been the focus of research in the field of rs-fMRI, which has revealed that MDD is a disorder characterized by widespread neural network dysfunction. This dysfunction has been primarily found in neural networks and regions associated with emotion regulation, including the default mode network (DMN), the salience network, the affective network, and the prefrontal cortex. Therefore, different aspects of negative thinking may be associated with abnormal resting-state neural networks.

For patients with repetitive negative thinking (RNT), dysfunctional connectivity has also been reported in resting-state networks, including altered connectivity with the left executive control network and the anterior salience network and the ventral default mode network.

Thus, patients suffering from negative thinking exhibit alterations in functional connectivity within and/or between resting-state neural networks compared to healthy, age-matched controls. Alterations are observed within and/or between the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

In many cases, RSNs involved in negative thinking are affected by mental or neurological disorders, such as disorders characterized by depressive episodes, such as major depressive disorder [MDD], bipolar disorders [BD], such as bipolar I disorder and bipolar II disorder, postpartum depression [PPD], seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder [GAD] and social anxiety disorder [SAD]; obsessive-compulsive and related disorders, such as obsessive-compulsive disorder [OCD] and body dysmorphic disorder [BDD]; posttraumatic stress disorder [PTSD]; pain disorders, such as chronic pain; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders [SUD]; psychotic disorders, such as schizophrenia; dementias, such as Alzheimer's dementia (AD); eating disorders; attention-deficit/hyperactivity disorder [ADHD]; and personality disorders, such as schizotypal personality disorder and borderline personality disorder [BPD].

The resting-state neural networks involved in negative thinking are also affected by mental or neurological conditions that result from certain medical health conditions, such as traumatic brain injury [TBI].

The resting-state neural network associated with negative thinking is also affected by sleep disorders, such as insomnia. In fact, there is a correlation between negative thinking and sleep disturbances.

Treatment of negative thinking and mental or nervous disorders

According to the present invention, negative thinking can be treated in patients suffering from mental or nervous system disorders. Furthermore, negative thinking can be treated in patients suffering from sleep disorders, such as insomnia.

As described in detail above, in patients suffering from negative thinking associated with other conditions, treatment of negative thinking according to the present invention results in improvement of the condition associated with the negative thinking.

Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and/or between neural networks at rest. This disruption reestablishes pathologically miswired connections when the neural network reconnects. New, healthy functional connections are established with lasting effects.

Accordingly, according to the present invention, influencing these neural networks by the therapy described herein will result in an improvement in negative thinking, and if the treated patient suffers from a mental or neurological disorder, it will also result in an improvement in that disorder; and if the treated patient suffers from a sleep disorder, for example, insomnia, it will also result in an improvement in the sleep disorder, for example, insomnia.

To further support the clinical application of 5-MeO-DMT in patients suffering from negative thinking, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in negative thinking that were typically also observed in patients with other disorders.

These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). While TRD is a unique condition, the inventors have identified specific clinical observations from the trial as relevant for designing treatments for other conditions associated with negative thinking, as discussed in detail below.

In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized daily dosing regimen (IDR), which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) within a day based on the intensity of the patient's reported hallucinatory experience, are of interest.

The collected data included treated patients' ratings on several scales, including the Montgomery-Osberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on items across various rating scales, noting that specific subscale items, such as those related to negative thinking, have been linked to other conditions based on similarly altered functional connectivity within and/or between the default mode neural network, executive control neural network, salience neural network, affective neural network, and prefrontal cortex.

A significant improvement was observed in a large number of patients within the recruited cohort, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

More specifically, aspects that can be treated by administration of 5-MeO-DMT include negative thinking, particularly feelings of worthlessness, helplessness, and hopelessness, and/or guilt. Administration of 5-MeO-DMT to a patient can reduce or eliminate negative thinking, particularly feelings of worthlessness, helplessness, and hopelessness, and/or guilt.

The MADRS scale item that is particularly relevant to negative thinking is 'pessimistic thinking,' which represents thoughts of guilt, inferiority, self-reproach, sin, regret, and doom.

A score of 0 is given for the absence of pessimistic thoughts. A score of 2 is given for fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 6 indicates that the patient is increasingly pessimistic about the future, as well as persistent self-blame, or thoughts of certain but still reasonable guilt or sin. A score of 6 is given for delusions of doom, regret, or irredeemable sin, and unreasonable and unwavering self-blame.

In the study group receiving individualized dosing regimens, the aggregate score for the MADRS item 'pessimistic thinking' across all eight patients was 28 at baseline.

After 2 hours, this decreased to 7, corresponding to a 21-point or 75% improvement. On the first day after treatment, this decreased to 4, corresponding to a 24-point or 86% improvement. On the seventh day after treatment, this decreased to 3, corresponding to a 25-point or 89% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Pessimistic Thinking' was 16 at baseline across all four patients. After 2 hours, this had decreased to 8, corresponding to an 8-point or 50% improvement. On day 1 post-treatment, this had decreased to 7, corresponding to a 9-point or 56% improvement.

On day 7 after treatment, this was reduced to 8, corresponding to an improvement of 8 points or 50%.

The BPRS item particularly associated with negative thinking is "Feelings of Guilt." This item concerns excessive concern or regret about past behavior. Possible scores are as follows:

1 - No feeling of guilt.

2 - Very mild. Concerned about failing at something or someone, but not preoccupied. Thoughts can easily shift to other concerns.

3 - Mild. Concerns about failing at something or someone, with some preoccupation. Tends to blame others.

4 - Moderate. Excessive preoccupation with guilt, wrongdoing, or hurting others through actions or omissions, but can easily be distracted.

5 - Moderately severe. If you are preoccupied with guilt over failing someone or something, you can shift your attention to something else, but it requires significant effort. You are not delusional.

6 - Severe; Delusional guilt or irrational self-blame that is excessive and disproportionate to the situation. Moderate obsession.

7 - Extremely severe. Delusional guilt or irrational self-blame that is excessive and disproportionate to the situation. The subject is deeply preoccupied with guilt and may confide in others or act on the delusion.

In the study group receiving individualized dosing regimens, the aggregate score for the BPRS item 'Feelings of guilt' across all eight patients was 34 at baseline.

After 3 hours, this decreased to 14, corresponding to a 20-point or 59% improvement. On the first day after treatment, this decreased to 11, corresponding to a 23-point or 68% improvement. On the seventh day after treatment, this decreased to 10, corresponding to a 24-point or 71% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Feelings of guilt' across all four patients was 18 at baseline.

After 3 hours, this decreased to 9, corresponding to a 9-point or 50% improvement. On the first day after treatment, this decreased to 5, corresponding to a 13-point or 72% improvement. On the seventh day after treatment, this decreased to 5, corresponding to a 13-point or 72% improvement.

Therefore, scores on the MADRS scale item "Pessimistic Thinking," which is particularly related to negative thinking, significantly improved, as did scores on the BPRS item "Guilt." The inventors concluded that 5-MeO-DMT can be used to treat negative thinking in patients, particularly those suffering from mental or neurological disorders or sleep disorders such as insomnia.

Consequently, according to the present invention, treating a patient suffering from negative thinking with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the negative thinking.

maternal function

In addition to the above, the inventors believe that mental or neurological disorders, as defined herein, particularly disorders involving one or more symptoms selected from sleep disturbances, cognitive dysfunction, anxiety, psychomotor delay, social/emotional withdrawal, and negative thinking, impair maternal functioning. Indeed, each of the symptoms listed has the potential to impair maternal functioning (and therefore deserves to be treated independently).

The first year after birth is a particularly crucial time for both mother and child. In most cases, mothers are the primary caregivers and thus bear the brunt of the infant caregiving responsibilities.

Maternal functioning includes aspects of maternal competence related to maternal self-care as well as interactions with the infant(s).

Maternal functioning, including maternal emotional aspects, is also crucial for infant development. Indeed, the quality of mother-infant interaction within the first year of life influences infant development. High levels of maternal functioning are likely to be correlated with positive infant developmental outcomes. Similarly, functional impairments during the postpartum period may impede optimal infant development.

The Barkin Maternal Function Index (BIMF) was designed to measure functioning within the first year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is scored from 0 to 6, for a maximum total score of 120. Higher scores indicate better maternal functioning.

The BIMF identifies the following key functional domains for mothers during the postpartum period: self-care, infant care, mother-infant interaction, maternal psychosocial well-being, social support, and management and adaptation.

A BIMF score of 95 or less is considered herein to indicate mildly impaired maternal function, a score of 80 or less is considered herein to indicate severely impaired maternal function, and a score of 65 or less is considered herein to indicate severely impaired maternal function. In particular, the present invention allows for improving maternal function in patients with a score of 80 or less prior to treatment, and even in patients with a score of 65 or less.

As previously described, the present invention enables the treatment of patients suffering from mental or neurological disorders. This treatment not only leads to a reduction in scores assessing the severity of depression, but also improves maternal function, as discussed in detail below.

To further support the clinical application of 5-MeO-DMT in patients with psychiatric or neurological disorders, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in disease manifestations typically observed in patients with psychiatric or neurological disorders. The inventors particularly noted improvements in various symptoms and combinations of symptoms that the inventors identified as also being associated with maternal function.

These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). These results were confirmed by a recent trial in patients with postpartum depression (see the Examples section below).

In the TRD clinical trial, 5-MeO-DMT was administered via inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group receiving a single 12 mg dose and the group receiving an individualized daily dosing regimen (IDR), which allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) within a day based on the intensity of the patient's reported hallucinatory experience, are of interest.

The collected data included assessments of treated patients on several scales, including the Montgomery-Osberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the investigators focused on items included in various rating scales, noting that several subscales were particularly relevant to patients with psychiatric or neurological disorders and were associated with maternal functioning.

Multiple patients within the recruited cohort showed significant improvement in one or more of these subscales, confirming the inventors' finding that 5-MeO-DMT is a suitable compound for treating patients with psychiatric or neurological disorders and improving maternal function in such patients.

The specific subscale items for each scale are identified in more detail below. The inventors concluded that the efficacy of 5-MeO-DMT in treating one or more of these symptoms in patients with psychiatric or neurological disorders would result in a significant improvement in overall outcome.

Accordingly, the treatment according to the present invention reduces or eliminates (or improves or eliminates) aspects of the disease.

If a condition is assessed on the MADRS scale, it improves (reduces) by at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., the respective condition is scored as 0.

When a condition is assessed on the BPRS scale, it improves (reduces) by at least 1 point, or the patient is in complete remission (eliminated) after treatment, i.e., each condition is scored as 1.

Clinical response can also be reflected by a decrease in the Clinical Global Impression-Severity Scale (CGI-S) score. According to the present invention, a decrease in the CGI-S score means that the CGI-S has decreased by at least 1. Preferably, the CGI-S has decreased by at least 2 and/or has a score of 0. It is particularly preferred that the CGI-S has decreased by at least 3 and/or has a score of 0.

The inventors further believe that the improvements observed in specific MADRS items will translate into improvements in aspects of maternal function.

Particularly relevant MADRS items are described in more detail below.

The MADRS item " Inner Tension " describes feelings of mental tension that surge with undefined discomfort, irritability, inner turmoil, panic, fear, or distress. This is rated according to intensity, frequency, duration, and the degree of reassurance needed.

If the patient is calm and experiences only brief episodes of internal tension, a score of 0 is given. If the patient experiences occasional irritability and feelings of undefined discomfort, a score of 2 is given. If the patient experiences persistent internal tension or intermittent feelings of panic that can be overcome with only minor difficulty, a score of 4 is given. If the patient experiences constant fear or distress, or feelings of extreme panic, a score of 6 is given.

The present inventors found that increasing scores on the MADRS item "Internal Strain" negatively impacted both aspects of maternal functioning (maternal competence related to interaction with infant(s) and maternal self-care). Increased scores on the MADRS item "Internal Strain," as assessed by the BIMF, impaired not only mother-infant interaction but also maternal psychological well-being.

Conversely, improvements in these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and/or maternal psychosocial well-being.

In the study indicated above involving patients with TRD, the aggregate score for the MADRS item 'Internal Tension' across all eight patients in the study group receiving the individualized dosing regimen was 26 at baseline. Two hours later, this score decreased to 11 points, corresponding to a 15-point or 58% improvement. On day 1, this score decreased to 6 points, corresponding to a 20-point or 77% improvement. On day 7, this score decreased to 12 points, corresponding to a 14-point or 54% improvement.

The aggregated MADRS score for the "Inner Tension" item for all four patients in the 12 mg group was 13 at baseline. Two hours later, it decreased to 2, corresponding to an 11-point or 85% improvement. On day 1, it decreased to 3, corresponding to a 10-point or 77% improvement. On day 7, it decreased to 5, corresponding to an 8-point or 62% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or nervous disorders to achieve a reduction or elimination of internal tension.

Improvement in internal tension is reflected by an improvement in the MADRS item internal tension score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in internal tension, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in internal tension, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] or Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in internal tension, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably lasts for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that the reduction or elimination of internal tension achieved by treating patients with mental or neurological disorders would not only lead to a decrease in the MADRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; on the 7th day; on the 14th day; and/or on the 28th day.

Because internal tension also influences other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'Internal Tension' item of the MADRS would additionally contribute to overall improvements in maternal functioning.

The MADRS item ' Boredom ' indicates difficulty in starting daily activities or slowness in initiating and carrying them out.

A score of 0 indicates that the patient has little or no difficulty in starting activities and is not slow. If the patient has difficulty initiating activities, a score of 2 is given. A score of 4 indicates that the patient has difficulty initiating simple daily activities that require effort. A score of 6 indicates complete ennui, where the patient is unable to do anything without assistance.

The present inventors found that increasing scores on the MADRS item "Boredom" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. As scores on the MADRS item "Boredom" increased, infant care, self-care, psychosocial well-being, management, and adaptation were impaired.

Conversely, improvements in these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of infant care, self-care, psychosocial well-being, management, and/or adaptation.

In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item 'Meditation' across all eight patients was 27 at baseline. Two hours later, this had decreased to 10, corresponding to a 17-point or 63% improvement. On day 1 post-treatment, this had decreased to 5, corresponding to a 22-point or 81% improvement. On day 7 post-treatment, this had decreased to 3, corresponding to a 24-point or 89% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Malaise' was 16 at baseline across all four patients. Two hours later, this had decreased to 10, corresponding to a 6-point or 38% improvement. On day 1 post-treatment, this had decreased to 0, corresponding to a 16-point or 100% improvement. On day 7 post-treatment, this had decreased to 3, corresponding to a 13-point or 81% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to reduce or eliminate boredom.

Improvement in boredom is reflected by an improvement in the MADRS boredom score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in fatigue, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in fatigue, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in fatigue, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that a reduction or elimination of boredom achieved by treating patients with a psychiatric or neurological disorder would not only result in a decrease in the MADRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration. Since boredom also affects other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the 'boredom' item of the MADRS would additionally contribute to the overall improvement in maternal function.

The MADRS item " Alexithymia " describes the subjective experience of decreased interest in one's surroundings or in activities that are usually pleasurable. The ability to respond emotionally to situations or people is diminished.

A score of 0 indicates normal interest in one's surroundings and other people, a score of 2 indicates a reduced ability to enjoy usual interests, a score of 4 indicates a loss of interest in one's surroundings and a loss of feeling for friends and acquaintances, and a score of 6 reflects emotional numbness, an inability to feel anger, sadness, or joy, and a complete or even painful absence of feelings for close family and friends.

The present inventors found that increasing scores on the MADRS item "Sensational Alzheimer's" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with the infant(s) and maternal self-care. As scores on the MADRS item "Sensational Alzheimer's" increased, maternal-infant interaction and psychosocial well-being were impaired.

Conversely, improvements in this MADRS item lead to improvements in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and/or psychosocial well-being.

In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item 'Anesthesia' across all eight patients was 36 at baseline. Two hours later, this had decreased to 12 points, representing a 24-point or 67% improvement. On day 1 post-treatment, this had decreased to 2 points, representing a 34-point or 94% improvement. On day 7 post-treatment, this had decreased to 6 points, representing a 30-point or 83% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Anesthesia' across all four patients was 16 at baseline. Two hours later, this had decreased to 9, representing a 7-point or 44% improvement. On day 1 post-treatment, this had decreased to 1, representing a 15-point or 94% improvement. On day 7 post-treatment, this had decreased to 1, representing a 15-point or 94% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve reduction or elimination of sensory apathy.

Improvement in apathy is reflected by an improvement in the MADRS item apathy score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in apathy, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in apathy, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sensory apathy, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that a reduction or elimination of sensory ataxia achieved by treating patients with a psychiatric or neurological disorder would not only lead to a reduction in the MADRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed on days 7; 14; and/or 28 after the last administration.13 Since sensory ataxia also affects other aspects of psychiatric or neurological disorders, the inventors concluded that the improvements observed in the 'sensory ataxia' item of the MADRS would additionally contribute to the overall improvement in maternal function.

The MADRS item ' Difficulty concentrating ' indicates difficulty gathering thoughts and a lack of concentration that leaves one feeling helpless.

If the patient has no difficulty concentrating, the score is 0. If the patient occasionally has difficulty organizing thoughts, the score is 2. If the patient has difficulty concentrating and sustaining thoughts, which reduces their ability to read or converse, the score is 4. If the patient cannot read or converse without significant difficulty, the score is 6.

The present inventors found that increasing scores on the MADRS item "Difficulty Concentrating" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the MADRS item "Difficulty Concentrating" were associated with increased difficulties in infant and toddler care and management.

Conversely, improvements in these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functional domain of infant care and/or management.

In the study group receiving individualized dosing, the aggregated score for the MADRS item "Diminished Concentration" in all eight patients was 30 at baseline. Two hours later, this had decreased to 11 points, representing a 19-point improvement or 63% improvement. On day 1, this had decreased to 1 point, representing a 29-point improvement or 97% improvement. On day 7, this had decreased to 9 points, representing a 21-point improvement or 70% improvement.

In the 12 mg group, the aggregated score for the MADRS item "Diminished Concentration" in all four patients was 16 at baseline. Two hours later, this had decreased to 7, representing a 9-point improvement or 56% improvement. On day 1, this had decreased to 2, representing a 14-point improvement or 88% improvement. On day 7, this had decreased to 3, representing a 13-point improvement or 81% improvement.

The inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of difficulty in concentration.

Improvement in difficulty concentrating is reflected by an improvement in the MADRS item difficulty concentrating score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in concentration difficulties, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in difficulty concentrating, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in difficulty concentrating, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with psychiatric or neurological disorders with a reduction or elimination of concentration difficulties would not only result in a decrease in the MADRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within approximately 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed on days 7, 14, and/or 28 after the last administration.

Because difficulties with concentration also affect other aspects of mental or neurological disorders, we concluded that improvements observed in the 'Difficulties with Concentration' item of the MADRS would additionally contribute to overall improvements in maternal functioning.

The MADRS item ' Pessimistic Thinking ' represents thoughts of guilt, inferiority, self-reproach, sin, regret, and doom.

A score of 0 is given for the absence of pessimistic thoughts. A score of 2 is given for fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 6 indicates that the patient is increasingly pessimistic about the future, as well as persistent self-blame, or thoughts of certain but still reasonable guilt or sin. A score of 6 is given for delusions of doom, regret, or irredeemable sin, and unreasonable and unwavering self-blame.

The present inventors found that increasing scores on the MADRS item "Pessimistic Thinking" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the MADRS item "Pessimistic Thinking" were associated with impaired psychosocial well-being, social support, and self-management.

Conversely, improvements in these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functioning domains of psychological well-being, social support, and/or caregiving.

In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item 'Pessimistic Thinking' across all eight patients was 28 at baseline. Two hours later, this had decreased to 7, corresponding to a 21-point or 75% improvement. On day 1 post-treatment, this had decreased to 4, corresponding to a 24-point or 86% improvement. On day 7 post-treatment, this had decreased to 3, corresponding to a 25-point or 89% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Pessimistic Thinking' across all four patients was 16 at baseline. Two hours later, this had decreased to 8, corresponding to an 8-point or 50% improvement. On day 1 post-treatment, this had decreased to 7, corresponding to a 9-point or 56% improvement. On day 7 post-treatment, this had decreased to 8, corresponding to an 8-point or 50% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of pessimistic thinking.

Improvement in pessimistic thinking is reflected by an improvement in the MADRS pessimistic thinking score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in pessimistic thinking, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in pessimistic thinking, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in pessimistic thinking, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or the PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with mental or neurological disorders with a reduction or elimination of pessimistic thinking would not only lead to a decrease in the MADRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Because pessimistic thinking also influences other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'pessimistic thinking' item of the MADRS would additionally contribute to overall improvements in maternal functioning.

The MADRS item ' decreased sleep ' refers to the experience of decreased duration or depth of sleep compared to the subject's normal pattern when healthy.

A score of 0 indicates that the subject sleeps normally. A score of 2 indicates some difficulty falling asleep, or slightly reduced, light, or irregular sleep. A score of 4 indicates that sleep is reduced or interrupted by at least 2 hours. A score of 6 indicates less than 2 or 3 hours of sleep.

The present inventors found that increasing scores on the MADRS item "Reduced Sleep" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the MADRS item "Impaired Sleep" impair self-care, psychological well-being, and self-management.

Conversely, improvements on these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychosocial well-being, and/or management.

In the study group receiving individualized dosing, the aggregate score for the MADRS item "Reduced Sleep" across all eight patients was 25 at baseline. On Day 1 post-treatment, the earliest time point at which the treatment's impact on sleep could be assessed, this had decreased to 12 points, representing a 13-point or 52% improvement. On Day 7 post-treatment, this had decreased to 9 points, representing a 16-point or 64% improvement.

In the 12 mg group, the aggregate score for the MADRS item 'Reduced Sleep' was 12 at baseline across all four patients. On day 1 post-treatment, this decreased to 10, representing a 2-point or 17% improvement. On day 7 post-treatment, this decreased to 6, representing a 6-point or 50% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of reduced sleep.

A reduction or elimination of reduced sleep is reflected by an improvement in the score of the MADRS item Reduced Sleep on at least day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

Improvement in reduced sleep, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 24 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Improvement in decreased sleep, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in reduced sleep, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that reducing or eliminating decreased sleep by treating patients with psychiatric or neurological disorders would not only lead to a decrease in the MADRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as day 1, e.g., about 24 hours after the last administration; day 7; day 14; and/or day 28.

Because reduced sleep also affects other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'reduced sleep' item of the MADRS would additionally contribute to overall improvements in maternal functioning.

An additional aspect of mental or neurological disorders that can be treated by administration of 5-MeO-DMT is suicidal ideation . Administering 5-MeO-DMT to patients with mental or neurological disorders can reduce or eliminate suicidal ideation in such patients.

In the above-mentioned clinical studies involving the administration of 5-MeO-DMT, the MADRS item ‘suicidal ideation’ was evaluated, among others.

"Suicidal ideation" refers to feeling that life is not worth living, feeling that natural death would be welcomed, having suicidal thoughts, and/or preparing for suicide. The suicide attempt itself should not affect the rating of this MADRS item.

A score of 0 indicates that the patient enjoys life. A score of 2 indicates that the patient with a mental or neurological disorder is tired of life and/or only has fleeting suicidal thoughts. A score of 4 indicates that the patient feels they would be better off dead, that suicidal thoughts are common, and that suicide is considered a possible solution, but that the patient has no specific plan or intention. A score of 6 indicates that the patient has an explicit plan for suicide and/or is actively preparing for it.

This MADRS scale item is particularly relevant to suicidal ideation.

The present inventors found that increasing scores on the MADRS item "Suicidal Thoughts" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. As scores on the MADRS item "Suicidal Thoughts" increased, self-care, psychosocial well-being, and self-management were impaired.

Conversely, improvements on these MADRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychosocial well-being, and/or management.

In the study group receiving individualized dosing, the aggregate score for the MADRS item "Suicidal Thoughts" for all eight patients was 11 at baseline. Two hours later, this had decreased to 3 points, representing an 8-point or 73% improvement. On day 1 post-treatment, this had decreased to 1 point, representing a 10-point or 91% improvement. On day 7 post-treatment, this had decreased to 3 points, representing an 8-point or 73% improvement.

In the 12 mg group, the aggregate score for the MADRS item "Suicidal Thoughts" for all four patients was 8 at baseline. Two hours later, this had decreased to 3, representing a 5-point or 63% improvement. On day 1 post-treatment, this had decreased to 5, representing a 38% or 3-point improvement. On day 7 post-treatment, this had decreased to 7, representing a 1-point or 13% improvement.

Therefore, scores on the "suicidal ideation" scale, a scale item particularly associated with suicidal ideation, significantly improved, at least in patients receiving individualized dosing. We conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with psychiatric or neurological disorders.

Therefore, according to the present invention, treatment of a patient with a mental or neurological disorder suffering from suicidal ideation reduces or eliminates the suicidal ideation.

A reduction or elimination of suicidal ideation is reflected by an improvement in the MADRS item suicidal ideation score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

If the patient is suffering from suicidal ideation, improvement in suicidal ideation is reflected by a decrease in the Clinical Global Impression-Severity Scale [CGI-S] score at approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in suicidal ideation, as assessed by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [CGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in suicidal ideation, as assessed by a decrease in the CGI-S score or a score of at least 'much improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with psychiatric or neurological disorders with a reduction or elimination of suicidal ideation would not only result in a decrease in the MADRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Because suicidal ideation also affects other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'suicidal ideation' item of the MADRS would additionally contribute to overall improvements in maternal functioning.

The BPRS item " Emotional Withdrawal " relates to the patient's inability to engage emotionally during the interview. Possible scores are:

1 - No emotional withdrawal.

2 - Very mild. Lacks emotional engagement, sometimes not offering feedback, sometimes appearing preoccupied, or laughing awkwardly, but most of the time, the interviewer interacts spontaneously.

3 - Mild. Lacks emotional engagement, appears visibly absent from the conversation, appears preoccupied, or lacks warmth, but responds when approached by the interviewer.

4 - Moderate. There is little emotional connection during the interview, as the subject may not respond in detail, fail to make eye contact, appear unconcerned with the interviewer, or become preoccupied with psychotic material.

5 - Moderately severe. Same as '4', but there is no emotional contact for most of the interview.

6 - Severe. Actively avoids emotional involvement. Frequently responds inactively or with yes/no answers (not simply due to persecutory delusions). Responds only with minimal impact.

7 - Extremely severe. Persistently avoids emotional engagement. Does not respond or gives yes/no answers (not simply due to persecutory delusions). Leaves the interview or does not respond at all.

The present inventors found that increasing scores on the BPRS item "Emotional Withdrawal" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the BPRS item "Emotional Withdrawal" were associated with impaired psychosocial well-being, maternal-infant interaction, and social support.

Conversely, improvements in these BPRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychosocial well-being, mother-child interaction, and/or social support.

In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "Emotional Withdrawal" was 13 at baseline. Three hours later, this score decreased to 8, representing a 5-point or 38% improvement. On day 1 post-treatment, this score decreased to 8, representing a 5-point or 38% improvement. On day 7 post-treatment, this score decreased to 8, representing a 5-point or 38% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Emotional Withdrawal' was 13 at baseline. After 3 hours, this had decreased to 11, representing a 2-point or 15% improvement. On day 1 post-treatment, this had decreased to 8, representing a 5-point or 38% improvement. On day 7 post-treatment, this had decreased to 6, representing a 7-point or 54% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve reduction or elimination of emotional withdrawal.

A reduction or elimination of emotional withdrawal is reflected by an improvement in the BPRS item emotional withdrawal score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in emotional withdrawal, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in emotional withdrawal, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in emotional withdrawal, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with psychiatric or neurological disorders with a reduction or elimination of emotional withdrawal would not only result in a decrease in the BPRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Because emotional withdrawal also affects other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'emotional withdrawal' item of the BPRS would additionally contribute to overall improvements in maternal functioning.

The BPRS item "Blunt Affect" is associated with a limited range of emotional expression in the face, voice, and gestures, as well as marked indifference or flatness when discussing painful topics. Possible scores are:

1 - No dulled emotions.

2 - Very mild. Emotions are slightly subdued or reserved, but appropriate facial expressions and vocal tones are within normal limits.

3 - Mild. Overall emotional range is reduced, subdued, or reserved, with few spontaneous and appropriate emotional responses. The tone of voice is somewhat monotonous.

4 - Moderate. The emotional range is markedly reduced, and the patient displays little emotion, rarely smiles, and responds sparingly to distressing topics. The tone of voice is monotonous, and spontaneous movements are markedly reduced. After the emotion or gesture is expressed, the patient usually returns to a blunted affect.

5 - Moderately severe. The emotional range is greatly reduced, and the patient rarely expresses emotion, laughs, or responds to painful topics except for a few minimal gestures. Facial expressions are infrequently altered. The voice tone is often monotonous.

6 - Severe. There is little emotional range or expression. Speech and gestures are often mechanical. Facial expressions are unchanging. Voice tone is often monotonous.

7 - Extremely severe. There is little emotional range or expressiveness, and movements are stiff. The voice tone is always monotonous.

We found that increasing scores on the BPRS item "Blunted Affect" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with the infant(s) and maternal self-care. Increased scores on the BPRS item "Blunted Affect" were associated with impaired psychosocial well-being and maternal-infant interaction.

Conversely, improvements in these BPRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychosocial well-being and/or mother-infant interaction.

The aggregate score for the BPRS item "Blunt Affect" was 15 at baseline. Three hours later, this had decreased to 11, representing a 4-point or 27% improvement. On day 1 post-treatment, this had decreased to 8, representing a 7-point or 47% improvement. On day 7 post-treatment, this had decreased to 8, representing a 7-point or 47% improvement.

In the 12 mg group, the aggregate score for the BPRS item "Blunt Affect" was 11 points at baseline. Three hours later, this had decreased to 8 points, representing a 3-point or 27% improvement. On day 1 post-treatment, this had decreased to 6 points, representing a 5-point or 45% improvement. On day 7 post-treatment, this had decreased to 5 points, representing a 6-point or 55% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve reduction or elimination of blunted affect.

A reduction or elimination of blunted affect is reflected by an improvement in the BPRS item blunted affect score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in blunted affect, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in blunted affect, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in blunted affect, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably lasts for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that reducing or eliminating blunted affect by treating patients with psychiatric or neurological disorders would not only lead to a decrease in the BPRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Because blunted affect also influences other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'blunted affect' item of the BPRS would additionally contribute to overall improvements in maternal functioning.

The BPRS item " Feelings of Guilt " concerns excessive concern or regret about past behavior. Possible scores are:

1 - No feeling of guilt.

2 - Very mild. Concerned about failing at something or someone, but not preoccupied. Thoughts can easily shift to other concerns.

3 - Mild. Concerns about failing at something or someone, with some preoccupation. Tends to blame others.

4 - Moderate. Excessive preoccupation with guilt, wrongdoing, or hurting others through actions or omissions, but can easily be distracted.

5 - Moderately severe. If you are preoccupied with guilt over failing someone or something, you can shift your attention to something else, but it requires significant effort. You are not delusional.

6 - Severe. Delusional guilt or remorse that is irrational compared to the situation. Moderate obsession.

7 - Extremely severe. Delusional guilt or irrational self-blame that is excessive and disproportionate to the situation. The subject is deeply preoccupied with guilt and may confide in others or act on the delusion.

The present inventors found that increasing scores on the BPRS item "Feelings of Guilt" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the BPRS item "Feelings of Guilt" were associated with impaired self-care, mother-infant interaction, psychosocial well-being, and management.

Conversely, improvements in these BPRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, mother-child interaction, psychosocial well-being, and/or management.

In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "Feelings of Guilt" across all eight patients was 34 at baseline. Three hours later, this had decreased to 14, corresponding to a 20-point or 59% improvement. On day 1 post-treatment, this had decreased to 11, corresponding to a 23-point or 68% improvement. On day 7 post-treatment, this had decreased to 10, corresponding to a 24-point or 71% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Feelings of Guilt' across all four patients was 18 at baseline. Three hours later, this had decreased to 9, corresponding to a 9-point or 50% improvement. On day 1 post-treatment, this had decreased to 5, corresponding to a 13-point or 72% improvement. On day 7 post-treatment, this had decreased to 5, corresponding to a 13-point or 72% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of feelings of guilt.

A reduction or elimination of feelings of guilt is reflected by an improvement in the score of the BPRS item Feelings of Guilt at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in feelings of guilt, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in feelings of guilt, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in feelings of guilt, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with mental or neurological disorders with a reduction or elimination of feelings of guilt would not only lead to a decrease in the BPRS total score, but also to an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Since feelings of guilt also influence other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'Feelings of Guilt' item of the BPRS would additionally contribute to overall improvements in maternal functioning.

The BPRS item " Anxiety " relates to reported feelings of anxiety, tension, fear, panic, or worry. Possible scores are:

1 - No anxiety.

2 - Very mild. Most normal people report some discomfort due to worries that occur more frequently than usual or are rare.

3 - Mild. Frequently anxious, but easily distracted by other things.

4 - Moderate. Mostly anxious and easily distracted, but no functional impairment, or occasionally anxious with autonomic nervous system involvement, but no functional impairment.

5 - Moderately severe. Frequent but not daily periods of anxiety accompanied by autonomic dysfunction, or some areas of functioning are disrupted by anxiety or worry.

6 - Severe. Anxiety accompanied by autonomic dysfunction is present daily, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or constant worry.

7 - Extremely severe. Anxiety accompanied by autonomic dysfunction persists throughout the day, or most areas of functioning are disrupted by anxiety or constant worry.

The present inventors found that increasing scores on the BPRS item "Anxiety" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. Increased scores on the BPRS item "Anxiety" were associated with impaired psychosocial well-being, social support, and self-management.

Conversely, improvements in these BPRS items lead to improvements in maternal functioning, particularly in the BIMF functioning domains of psychological well-being, social support, and/or caregiving.

In the study group receiving individualized dosing, the aggregate score for the BPRS item 'Anxiety' across all eight patients was 37 at baseline. Three hours later, this score decreased to 19, corresponding to an 18-point or 49% improvement. On day 1, this score decreased to 16, corresponding to a 21-point or 57% improvement. On day 7, this score decreased to 17, corresponding to a 20-point or 54% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Anxiety' across all four patients was 25 at baseline. At 3 hours, this decreased to 11 points, corresponding to a 14-point or 56% improvement. On day 1, this decreased to 6 points, corresponding to a 19-point or 76% improvement. On day 7, this decreased to 6 points, corresponding to a 19-point or 76% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve reduction or elimination of anxiety.

A reduction or elimination of anxiety is reflected by an improvement in the BPRS anxiety score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in anxiety, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] or Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in anxiety, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with psychiatric or neurological disorders with a reduction or elimination of anxiety would not only result in a decrease in the BPRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Since anxiety also influences other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'Anxiety' item of the BPRS would additionally contribute to overall improvements in maternal functioning.

The BPRS item ' Tension ' refers to observable physical and motor signs of tension, nervousness, and agitation. Possible scores are:

1 - No tension.

2 - Very mild. More fidgety than most, but within normal range. Some temporary signs of nervousness, such as fingernail picking, foot shaking, scalp scratching, or finger tapping.

3 - Mild. Same as '2', but signs of tension are more frequent or exaggerated.

4 - Moderate. Signs of motor tension are numerous and frequent, with one or more signs sometimes occurring simultaneously. For example, wringing and clenching hands, shaking feet, etc. In some cases, no signs of tension are present at all.

5 - Moderately severe. Signs of motor tension are numerous and frequent, with more than one sign often occurring simultaneously. Rarely, signs of tension are absent altogether.

6 - Severe. Same as '5', but signs of tension persist.

7 - Extremely severe. Multiple motor signs of tension are persistent, such as persistent pacing and hand wringing.

The present inventors found that increasing scores on the BPRS item "Tension" negatively impacted two aspects of maternal functioning: maternal competence related to interaction with infant(s) and maternal self-care. As scores on the BPRS item "Tension" increased, maternal-infant interaction and psychological well-being were impaired.

Conversely, improvements in these BPRS items lead to improvements in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and/or psychosocial well-being.

In the study group receiving individualized dosing, the aggregate score for the BPRS item 'Tension' across all eight patients was 16 at baseline. After 3 hours, this had decreased to 11, corresponding to a 5-point or 31% improvement. On day 1 post-treatment, this had decreased to 11, corresponding to a 5-point or 31% improvement. On day 7 post-treatment, this had decreased to 6, corresponding to a 10-point or 38% improvement.

In the 12 mg group, the aggregate score for the BPRS item 'Tension' across all four patients was 14 at baseline. Three hours later, this had decreased to 9, corresponding to a 5-point or 36% improvement. On day 1 post-treatment, this had decreased to 6, corresponding to an 8-point or 57% improvement. On day 7 post-treatment, this had decreased to 6, corresponding to an 8-point or 57% improvement.

The present inventors concluded that 5-MeO-DMT can be used to treat patients with mental or nervous disorders to achieve a reduction or elimination of tension.

A reduction or elimination of tension is reflected by an improvement in the score of the BPRS item fatigue at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours later; on day 7; on day 14; and/or on day 28.

Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] scores, occurs within approximately 2 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

Additionally or alternatively, a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in tension, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] or Patient Global Impression-Improvement [PGI-I] score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in tension, as reflected by a decrease in the CGI-S score or a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Furthermore, the inventors concluded that treating patients with psychiatric or neurological disorders with a reduction or elimination of tension would not only result in a decrease in the BPRS total score, but also in improved maternal function, as reflected by an increase in the BIMF score. This improvement would be achieved rapidly, i.e., within about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score would also be observed as early as 1 day, e.g., about 24 hours after the last administration; 7 days; 14 days; and/or 28 days after the last administration.

Since tension also influences other aspects of mental or neurological disorders, we concluded that the improvements observed in the 'tension' item of the BPRS would additionally contribute to overall improvements in maternal functioning.

Improvement in one or more aspects of a mental or neurological disorder will also result in overall improvement. Preferably, treatment leads to remission.

Remission of depressive symptoms will be reflected by a MADRS score of 10 or less, occurring within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and/or on day 28.

Alternatively or additionally, remission of depressive symptoms will be reflected by a HAM-D score of 7 or less, occurring, for example, within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, after about 24 hours; on day 7; on day 14; and/or on day 28.

From the above, it can be concluded that treatment of patients with psychiatric or neurological disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a decrease in the MADRS score, including the subscales described above, as well as improvements in domains of the BIMF scale. This decrease in the MADRS score, as well as improvements in maternal function, is confirmed by clinical data, as discussed in the Examples section below.

Improvement in maternal functioning includes improvements in the functional domain of self-care. For example, improvements in the MADRS items of boredom and/or reduced sleep lead to increases in the BIMF scale score, which reflects self-care. The cumulative score improvement in the BIMF scale items reflecting self-care is preferably at least 10%, and more preferably at least 20%.

Improvements in maternal functioning include improvements in the functional domain of infant care. For example, improvements in the MADRS items of boredom and/or difficulty concentrating lead to increases in the BIMF scale score, which reflects infant care. The cumulative score improvement in the BIMF scale items, which reflect self-care, is preferably at least 15%, and more preferably at least 25%.

Improvements in maternal functioning include improvements in the functional domain of mother-child interaction. For example, improvements in the MADRS items of alexithymia and internal tension lead to increases in the BIMF scale score, which reflects mother-child interaction. The cumulative score improvement in the BIMF scale items reflecting mother-child interaction is preferably at least 5%, and more preferably at least 15%.

Improvement in maternal functioning includes improvements in the functional domains of psychosocial well-being. For example, improvements in the MADRS items of boredom, pessimism, apathy, internal tension, and/or decreased sleep lead to increases in the BIMF scale score, which reflects psychosocial well-being. The cumulative score improvement in the BIMF scale items reflecting psychosocial well-being is preferably at least 25%, and more preferably at least 35%.

Improvements in maternal functioning include improvements in the functional domain of social support. For example, improvements in the MADRS item pessimistic thinking lead to increases in the BIMF scale score, which reflects social support. The cumulative score improvement in the BIMF scale items reflecting social support is preferably at least 10%, and more preferably at least 20%.

Improvement in maternal functioning includes improvements in the functional domain of management. For example, improvements in the MADRS items of boredom, pessimistic thinking, and/or difficulty concentrating lead to increases in the BIMF scale score, which reflects management. The cumulative score improvement in the BIMF scale items reflecting management is preferably at least 20%, and more preferably at least 30%.

Improvements in maternal functioning include improvements in the functional domain of adjustment. For example, improvements in the MADRS item of boredom lead to increases in the BIMF scale score, which reflects adjustment. The cumulative score improvement in the BIMF scale items reflecting adjustment is preferably at least 5%, and more preferably at least 15%.

Improvements in maternal functioning were associated with one or more, and specifically two, functional domains selected from the Barkin Index of Maternal Functioning (BIMF) from self-care, infant care, mother-infant interaction, maternal psychosocial well-being, social support, management, and adaptation.

The BIMF total score improves by at least 10%, preferably by at least 20%.

breastfeeding

As used herein, breastfeeding refers to the process of feeding breast milk to an infant. Breastfeeding includes both direct breastfeeding and bottle-feeding of previously expressed breast milk.

As noted above, for many medications, breastfeeding patients may be faced with the decision of whether to discontinue breastfeeding or discontinue/abstain from therapy.

If a decision is made to discontinue breastfeeding in order to receive treatment, this decision will have a negative impact on maternal functioning, particularly in the functional domains of mother-infant interaction and psychosocial well-being.

The present invention also addresses the need to treat mental or neurological disorders in lactating mothers without substantially discontinuing breastfeeding.

According to the present invention, breastfeeding can be resumed immediately after treatment.

The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT to determine at what point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt, breastfeeding is possible without exposing the infant to any associated risks.

Additionally, breast milk was obtained from breastfeeding patients treated with 5-MeO-DMT for PPD. As described in more detail in the Examples section, breastfeeding patients with PPD were administered a 6 mg dose of 5-MeO-DMT, followed by a further 12 mg dose of 5-MeO-DMT 1 hour later.

Breast milk samples, as well as serum and urine samples, were analyzed for 5-MeO-DMT, bufotenine (the major metabolite of 5-MeO-DMT), and 5-MIAA (the final metabolite of 5-MeO-DMT) at various time points after the last dose of 5-MeO-DMT.

The administered compound, 5-MeO-DMT itself, is rapidly absorbed and distributed, with peak concentrations and pharmacological effects observed during and immediately after administration, for example, by inhalation or injection.

Plasma protein binding is low (13 to 23%).

Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. As early as 10 minutes after administration, concentrations fall below 10% of Cmax, 2 hours later, they are below 1% of Cmax, and 3 hours later, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within the 1- to 4-hour time frame. The dose escalation regimen described herein does not lead to accumulation of 5-MeO-DMT and therefore will not result in higher plasma concentrations at 10 minutes, 2 hours, or 3 hours after administration.

The rapid decrease in plasma concentrations occurs as a result of the very short time that 5-MeO-DMT can be absorbed into breast milk. Therefore, 5-MeO-DMT will only be found in breast milk for a short period of time.

Collected patient data confirm a rapid decrease in 5-MeO-DMT concentrations in breast milk (see Example 12). Measurements after 24 hours did not detect any 5-MeO-DMT.

When determining the potential effects of maternal drug administration on a breastfed infant, it is standard practice to calculate the relative infant dose (RID) (Bennett, PN, and LJ Notarianni. "Risk from drugs in breast milk: an analysis by relative dose." Br J Clin Pharmacol 42.5 (1996): P673-4). The RID is the dose to which the infant is exposed through breast milk (in μg/kg/day) divided by the dose to which the mother receives (in μg/kg/day).

Estimates of daily breast milk intake and the number of feedings, as well as measured breast milk concentrations, can be used to determine infant exposure.

For example, a published estimate of daily breast milk intake as a function of infant weight is 150 ml/kg/day. To model exposure, assume that a 5 kg infant is fed three times over a 24-hour period, receiving 250 ml of breast milk at each feeding. During the first feeding, the 5-MeO-DMT concentration is assumed to be 2167.0 pg/ml (determined at 1 hour), 560.6 pg/ml (determined at 2.5 hours) for the second feeding, and 42.1 pg/ml (determined at 8.5 hours) for the third feeding. Based on this, the total infant exposure (infant daily dose, DID) is 692425 pg 5-MeO-DMT/day (0.000692425 mg/day), which corresponds to 0.000138485 mg/kg/day.

Regarding maternal 5-MeO-DMT exposure, the total dose was 18 mg (6 mg as the first dose and 12 mg as the second dose, according to the applied dose escalation schedule).

Since the amount actually delivered to the patient may be lower than the suggested dose, the RID calculation is also performed assuming that the actual delivered amount is only 50% of the suggested dose to avoid a possible underestimation of infant exposure.

Assuming a standard maternal body weight of 60 kg, an RID of 0.092% (based on 9 mg as maternal exposure) to 0.046% (based on 18 mg as maternal exposure) is obtained.

The accepted threshold for a 'low-risk' RID is 10%. The calculated values clearly indicate that the RID for 5-MeO-DMT is significantly lower than this threshold.

It should also be noted that the range of 0.046% to 0.092% is a conservative estimate. It assumes that 5-MeO-DMT concentrations remain constant between feedings (despite the rapid decline in actual concentrations), and ignores the fact that infants are likely to be fed more than three times per day, with each feeding decreasing in volume, exposing them to decreasing concentrations of 5-MeO-DMT over time.

Additionally, these estimates assume that breast milk is expressed and not discarded.

Therefore, the actual RID will be lower than the estimate.

Metabolites of 5-MeO-DMT that can occur in humans were identified to assess their potential relevance. In an in vitro metabolic identification study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below:

It was noted that subsequent assays repeatedly failed to detect the presence of 5-methoxytryptopol, but reproducibly demonstrated the presence of 5-MIAA as a major metabolite. 5-methoxytryptopol is unlikely to play any significant role in vivo.

Metabolites listed in the table above are formed through three different pathways.

The two most significant metabolites, 5-methoxyindole acetic acid and 5-methoxyindole-3-ethanol, are formed through oxidative deamination, which involves enzymatic removal and oxidation of the N-methyl group, resulting in the formation of acetaldehyde, as shown below.

The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

Secondary amines, primary amines and aldehydes were not identified, indicating that they were not present in significant concentrations at any time.

The aldehyde intermediate metabolite undergoes two separate biotransformations in human liver cells: it is either oxidized to 5-methoxyindole acetic acid (5-MIAA) or reduced to 5-methoxyindole-3-ethanol.

Both metabolites produced are endogenous and are formed in the human body during the synthesis and metabolism of, for example, melatonin and serotonin (see, e.g., Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).

Because the predominant pathway of 5-MeO-DMT metabolism also rapidly leads to metabolites that are part of the endogenous metabolic pathway, the inventors determined that oxidative deamination of 5-MeO-DMT does not entail the formation of metabolites that would require restrictions on breastfeeding.

Moreover, as detailed in the Examples section, incubation of 5-methoxytryptopol with human hepatocytes demonstrated a high metabolic turnover rate, with complete disappearance of the compound within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance rate for 5-methoxytryptopol was 16.2 μl/min/million cells (half-life of 142 minutes).

Therefore, the plasma concentration of 5-methoxytryptopol will rapidly decrease to the extent that it is formed and reach endogenous levels.

5-MIAA has been identified as a major human metabolite.

Human hepatocytes and 5-MIAA exhibited low metabolic turnover, with residual 5-MIAA concentrations ranging from 75 to 82% after 72 hours. 5-MIAA is considered to be the final metabolite of 5-MeO-DMT.

5-MIAA exhibits relatively low plasma binding of approximately 50% (mean unbound fraction (Fu); see Examples section). It remains in the circulation after renal clearance.

If we ignore endogenous production of 5-MIAA and assume that 5-MIAA is produced immediately from this compound after a single dose of 5-MeO-DMT, a standard glomerular filtration rate of 90 to 120 ml/min suggests that 5-MIAA is excreted in the urine within approximately 1 to 2 hours.

For example, the 5-MIAA urine concentration determined after 2.5 hours was 12 980 501 pg/ml (approximately 12.98 mg/l), indicating that most of the formed 5-MIAA was rapidly excreted.

As a result, plasma concentrations of 5-MIAA will decrease rapidly.

To more accurately estimate changes in plasma concentrations of 5-MIAA, several factors must be considered, including the patient's body size and the increased blood volume that occurs during pregnancy. It is understood that glomerular filtration rate and 5-MeO-DMT metabolism vary between individuals.

Furthermore, although 5-MIAA formation is rapid, pharmacokinetic data from healthy volunteers as well as PPD patients suggest that small amounts of 5-MeO-DMT (less than 10% of Cmax) may still be present after approximately 1 hour. Therefore, 5-MIAA formation likely occurs some time after 5-MeO-DMT administration.

Furthermore, when 5-MeO-DMT is administered in more than one dose, there will be no accumulation of 5-MeO-DMT if the interval between doses is at least about 1 hour, but since measurable amounts of 5-MIAA are still present in the serum at 2.5 hours, some accumulation of this metabolite will occur if the subject is administered at 1-hour intervals.

5-MIAA is a weak acid, which means it exists in plasma in an ionized form, which would reduce the likelihood that the compound would pass into breast milk.

Nonetheless, it is conceivable that some 5-MIAA will pass into breast milk, especially during limited periods when 5-MIAA plasma concentrations are relatively high.

Additional information on the concentration-time profile can be obtained from the measurement of 5-MIAA concentrations in breast milk presented in Example 12. These data can be used to estimate the infant's exposure to 5-MIAA.

During the first feeding of 250 ml, the 5-MIAA concentration is assumed to be 13945.2 pg/ml (determined at 1 hour), for the second feeding 13240.9 pg/ml (determined at 2.5 hours), and for the third feeding 359.4 pg/ml (determined at 8.5 hours). Based on this, the total infant exposure (DID) is 0.00688638 mg 5-MIAA/day, which corresponds to 0.00137728 mg/kg/day.

Because 5-MIAA concentrations in breast milk at 24 hours are almost 400 times lower than 1-hour concentrations, no relevant exposure is expected after 1 day.

Maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO-DMT administered and the rate at which 5-MeO-DMT is converted to 5-MIAA.

In the metabolic experiment described above, the mixture contained approximately 60% 5-MIAA after 2 hours. Since metabolism is not complete, the actual conversion of 5-MeO-DMT to 5-MIAA is likely higher. It is estimated that between 60% and nearly 100% of 5-MeO-DMT is converted to the final metabolite, 5-MIAA, and excreted from the body.

Considering the molecular weights (218.29 g/mol for 5-MeO-DMT and 205.21 g/mol for 5-MIAA), a total dose of 18 mg of 5-MeO-DMT leads to 10.15 mg of 5-MIAA (60% conversion) to 16.92 mg of 5-MIAA (100% conversion). Assuming that the amount of 5-MeO-DMT transferred as above is only 9 mg, 5.08 mg of 5-MIAA (60% conversion) to 8.46 mg of 5-MIAA (100% conversion) are formed.

Therefore, maternal exposure would be between 0.085 mg/kg/day and 0.282 mg/kg/day, representing an estimate of an RID of between 0.49% and 1.62%.

As presented, the acceptable threshold for a 'low-risk' RID is 10%, and it is clear from the calculated values that the 5-MIAA RID is significantly lower than this cutoff, which represents a conservative estimate.

Moreover, the risk profile for 5-MIAA is low, not only because it is below the daily RID threshold, but also because this compound is produced endogenously as a metabolite of certain naturally occurring tryptophan derivatives, such as serotonin.

Finally, levels of bufotenine, the major metabolite of 5-MeO-DMT, were assessed in urine, serum, and breast milk, as described in Example 12. Notably, bufotenine was not detected in serum or breast milk at any time point, but was detected in urine only at the 2.5-hour time point (32.3 pg/ml). These data further demonstrate that bufotenine does not affect the risk profile of 5-MeO-DMT.

The above calculations are based on a dose-escalation regimen involving 6 mg and 12 mg of 5-MeO-DMT. The conclusions drawn are also valid for single doses up to 12 mg, which would reduce exposure to 5-MeO-DMT and its metabolites.

Assuming a linear relationship between increasing dose and increasing milk concentrations and thus infant exposure, and extrapolating to higher doses, we conclude that the RID of 5-MeO-DMT and 5-MIAA would be significantly lower than 10% for lactating mothers treated with higher doses of 5-MeO-DMT, e.g., 18 mg or 25 mg as a single dose or as the final dose in a dose-escalation regimen.

This holds true even when considering the preservation effect of 5-MIAA in breast milk.

Linear extrapolation is justified based on the linear pharmacokinetic profile observed for 5-MeO-DMT.

Finally, when considering the risk to the infant, daily dosing should be considered, as it does not require consideration of the infant's cumulative exposure over a longer period of time as would be the case with chronic treatment regimens.

Another identified metabolite, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The resulting metabolite then undergoes glucuronidation catalyzed by UGTs, as follows:

As part of a pharmacokinetic study, it was confirmed that bufotenine was virtually undetectable in human serum. No traces were detected 15 minutes after administration of 5-MeO-DMT. A small amount was detected in urine after 2.5 hours (Example 12).

Bufotenine glucuronide cannot bind to receptors and exerts no effects. Furthermore, its concentration is so low that it cannot be detected in hepatocyte assays. Bufotenine glucuronide is further converted to 5-hydroxyindole acetic acid, as described below.

5-Hydroxyindole acetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (see above).

Since the O-demethylation pathway of 5-MeO-DMT plays only a minor role and leads to the major metabolite bufotenine, which is rapidly eliminated from plasma, and further metabolism leads to compounds present only in very low concentrations, ultimately metabolites that are also part of the endogenous metabolic pathway, the inventors have determined that the O-demethylation of 5-MeO-DMT does not entail metabolites that would require restrictions on breastfeeding.

The third metabolic pathway involves N-oxidation as follows:

In silico modeling of the formed metabolite, 5-MeO-DMT-N-oxide was considered non-genotoxic, consistent with the negative in vitro genotoxicity assessment of the parent molecule. This compound is water-soluble and rapidly excreted, as confirmed by observations in rats (Sitaram, B.R., Lockett, L., Blackman, G.L., McLeod, W.R., 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231). Since the pathway of 5-MeO-DMT metabolism involving N-oxidation plays only a minor role and results in a low proportion of metabolites with no apparent toxicity and are rapidly excreted, the inventors have determined that N-oxidation of 5-MeO-DMT does not result in metabolites that would require restrictions on breastfeeding.

Based on the above, the inventors determined that breastfeeding can be resumed immediately after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

It is safe for breastfeeding patients to temporarily discontinue breastfeeding. Generally, breastfeeding is not possible during the actual treatment period, i.e., during administration of 5-MeO-DMT or its pharmaceutically acceptable salts, and during the hallucinogenic experience following administration. However, once the effects wear off immediately after administration, breastfeeding patients can safely resume breastfeeding.

Early resumption of breastfeeding offers significant benefits to the nursing patient, her health, and the health of her baby.

A mother being treated may be advised to temporarily stop breastfeeding, for example, for a certain period of time or until certain circumstances occur.

Weaning from breastfeeding means not feeding your baby directly or expressing breast milk when breastfeeding is not recommended. However, previously collected breast milk can be bottle-fed. The timing of breast milk expression (not feeding to the baby) is the deciding factor.

Breastfeeding can be resumed after a specified period or event.

For example, mothers are advised to temporarily discontinue breastfeeding during the actual treatment period, for example, until the Clinical Assessment of Discharge Readiness (CADR) determines that the mother is ready for discharge.

A clinical assessment for discharge (CADR) is performed to ensure that there are no clinical barriers that would prevent the patient from returning home.

Readiness for discharge according to the CADR requires ensuring that all adverse events have resolved or, if unresolved, do not impede discharge; that the patient is fully oriented and free of hallucinations or perceptual distortions; that the patient is awake (easily responds to name in normal tones; 5 on the Modified Observer Rating of Arousal/Sedation); that there are no clinically significant changes in vital signs compared to baseline; and that the patient is ready for discharge in the judgment of the treating physician.

CADR can be performed approximately one hour after the last dose. Alternatively, a licensed professional can personally perform a discharge readiness assessment based on relevant factors such as the patient's arousal/sedation.

Patients may be advised not to resume breastfeeding before the later of discharge and 6 hours after the last dose, preferably 3 hours after the last dose after discharge; more preferably 2 hours after the last dose after discharge; and particularly 1 hour after discharge and the last dose, whichever is later.

You may wait longer before resuming breastfeeding, for example, until the concentration of 5-MeO-DMT and/or its metabolites in breast milk samples falls below a certain threshold.

For example, breastfeeding may be temporarily discontinued until the concentration of 5-MeO-DMT in breast milk samples falls below 2000 pg/ml, 500 pg/ml, or 75 pg/ml, or until the concentration of 5-MIAA in breast milk falls below 14000 pg/ml, 2000 pg/ml, or 75 pg/ml.

Alternatively, breast milk may be expressed and discarded until the 5-MeO-DMT and/or 5-MIAA concentrations fall below specified levels.

Additionally, breastfeeding may be temporarily discontinued for a period of time, for example, based on clinical experience with the concentration of 5-MeO-DMT and/or its metabolites in breast milk. In one example, the patient is advised to discontinue breastfeeding no later than 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The patient is preferably advised to discontinue breastfeeding no later than 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, more preferably no later than 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Even more preferably, breastfeeding should be discontinued for no longer than 6 hours, even more preferably no longer than 3 hours, especially no longer than 2 hours, and most preferably no longer than 1 hour, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

These brief interruptions and the corresponding possibility of resuming breastfeeding shortly after treatment contribute to the success of treatment, particularly maternal function and the well-being and development of the infant(s).

It is desirable that the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk be as low as possible to avoid any associated risks to the breastfeeding baby. If the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk exceeds a predetermined threshold, the expressed breast milk is discarded or breastfeeding is resumed only when the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk is below the predetermined threshold, any associated risks to the breastfeeding baby can be avoided. In a preferred embodiment, the threshold of 5-MeO-DMT in breast milk is as low as possible. In another preferred embodiment, the threshold of 5-MIAA in breast milk is as low as possible. In a most preferred embodiment, the threshold of both 5-MeO-DMT and 5-MIAA in breast milk is as low as possible.

The following provides various preferred thresholds for 5-MeO-DMT and/or 5-MIAA in breast milk.

Delivered Infant Dose (DID) for 5-MeO-DMT and/or 5-MIAA

The delivered infant dose [DID] for 5-MeO-DMT and/or 5-MIAA should be kept as low as possible. In a preferred embodiment, the DID for 5-MeO-DMT should be kept as low as possible. In a further preferred embodiment, the DID for 5-MIAA should be kept as low as possible. In a most preferred embodiment, the DID for both 5-MeO-DMT and 5-MIAA should be kept as low as possible.

The relevant DIDs for 5-MeO-DMT and/or 5-MIAA of the present invention are as follows.

To achieve the above DID, breastfeeding requires structure. This structure is determined by selecting the appropriate timing for breastfeeding resumption, the appropriate number of feedings during the first 24 hours after resumption, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA

The relative infant dose [RID] for 5-MeO-DMT and/or 5-MIAA should be kept as low as possible. In a preferred embodiment, the RID for 5-MeO-DMT should be kept as low as possible. In a further preferred embodiment, the RID for 5-MIAA should be kept as low as possible. In a most preferred embodiment, the RID for both 5-MeO-DMT and 5-MIAA should be kept as low as possible.

The relevant RIDs for 5-MeO-DMT and/or 5-MIAA of the present invention are as follows.

To achieve the above RID, breastfeeding requires structure. This structure is determined by selecting the appropriate timing for breastfeeding resumption, the appropriate number of feedings during the first 24 hours after resumption, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

Combination of delivered infant dose [DID] and relative infant dose [RID] for 5-MeO-DMT and/or 5-MIAA

DIDs and RIDs for 5-MeO-DMT and/or 5-MIAA are related aspects of the present invention. While each aspect is relevant in its own right, preferred embodiments of the present invention consider a combination of the two aspects, namely, DIDs for 5-MeO-DMT and/or 5-MIAA and RIDs for 5-MeO-DMT and/or 5-MIAA. Combinable related DIDs and related RIDs are provided in the present invention.

In one embodiment, the DID for 5-MeO-DMT and the RID for 5-MeO-DMT are combined. In a preferred embodiment, the DID and RID for 5-MeO-DMT should be kept as low as possible. The present invention provides a combinable related DID and related RID.

In a further embodiment, the DID for 5-MIAA and the RID for 5-MIAA are combined. In a preferred embodiment, the DID and RID for 5-MIAA should be kept as low as possible. The present invention provides a combinable related DID and related RID.

In a further embodiment, the DID for 5-MeO-DMT and the RID for 5-MIAA are combined. In a preferred embodiment, the DID for 5-MeO-DMT and the RID for 5-MIAA should be kept as low as possible. The present invention provides a combinable related DID and related RID.

In a further embodiment, the RID for 5-MeO-DMT and the DID for 5-MIAA are combined. In a preferred embodiment, the RID for 5-MeO-DMT and the DID for 5-MIAA should be kept as low as possible. The present invention provides a combinable related DID and related RID.

In a more preferred embodiment, the DID for 5-MeO-DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA are combined. In a preferred embodiment, the DID for 5-MeO-DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA should be kept as low as possible. The present invention provides a combination of related DIDs and related RIDs.

Treatment of mental or nervous system conditions

A disorder characterized by episodes of depression

There are several disorders characterized by depressive episodes.

A depressive episode is a period of depressed mood and/or loss of pleasure in most activities.

For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms that have existed during the same 2-week period and that represent a change from prior functioning; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

Patients suffering from disorders characterized by depressive episodes may suffer from treatment-resistant forms of the disorder.

Disorders characterized by depressive episodes involve one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with disorders characterized by depressive episodes, altered functional connectivity is observed within and/or between several brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; impaired attention, and physiological arousal.

Treatment of patients suffering from disorders characterized by depressive episodes, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the disorder characterized by depressive episodes.

Improvement in impairment characterized by a depressive episode, as reflected by a decrease in CGI-S scores, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's impairment characterized by a depressive episode occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the patient's impairment characterized by a depressive episode preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

An improvement in impairment characterized by a depressive episode, as reflected by a decrease in the MADRS score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the MADRS score, improvement in the patient's impairment characterized by a depressive episode occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the MADRS score, improvement in the patient's impairment characterized by a depressive episode preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

An improvement in impairment characterized by a depressive episode, as reflected by a decrease in the HAM-D score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the HAM-D score, improvement in the disorder characterized by a depressive episode in the patient occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the HAM-D score, improvement in the disorder characterized by a depressive episode preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients suffering from a disorder characterized by depressive episodes is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with a disorder characterized by a depressive episode occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Major depressive disorder (MDD) is a mood disorder characterized by persistent sadness and loss of interest. It affects how a person feels, thinks, and behaves, and can lead to a variety of emotional and physical problems.

Patients may have moderate or severe MDD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. Patients are also considered to have severe major depressive disorder, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale [HAM-D] score of 25 or greater.

Patients with MDD may have a treatment-resistant form of the disorder [TRD].

MDD involves one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, psychomotor delay, social/emotional withdrawal, and negative thinking.

Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with MDD, dysfunctional connectivity and modulation are observed within and/or between multiple resting-state neural networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

Treatment of patients with MDD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of MDD.

As reflected by a decrease in CGI-S scores, improvement in MDD is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's MDD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in MDD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in MDD, as reflected by a decrease in MADRS score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the MADRS score, improvement in the patient's MDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the MADRS score, improvement in MDD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in MDD, as reflected by a decrease in the HAM-D score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the HAM-D score, improvement in the patient's MDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the HAM-D score, improvement in MDD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with MDD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with MDD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

persistent depressive disorder

Persistent depressive disorder, also known as dysthymia, is a form of chronic depression. It is diagnosed when depressed mood persists most days for at least two years. Any symptom-free period lasts less than two months.

If you have depression, you must have at least two of the following: 1. Feelings of hopelessness; 2. Lack of energy or fatigue; 3. Low self-esteem; 4. Sleeping less (insomnia) or more (hypersomnia); 5. Loss of appetite or overeating; 6. Difficulty making decisions or concentrating.

Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

Persistent depressive disorder is characterized by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with persistent depressive disorder, functional connectivity changes are observed within and/or between several brain regions involved in processing, regulation, emotional memory, cognitive processes related to rumination, and impaired attention and physiological arousal. Dysfunctional connectivity is observed within and/or between the DMN, the salience network, the executive control network, and the limbic network. Functional connectivity differs significantly from that observed in healthy controls.

Treatment of patients with persistent depressive disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the persistent depressive disorder.

Improvement in persistent depressive disorder, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, approximately 24 hours after; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's persistent depressive disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the patient's persistent depressive disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in persistent depressive disorder, as reflected by a decrease in MADRS scores, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the MADRS score, improvement in the patient's persistent depressive disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the MADRS score, improvement in the patient's persistent depressive disorder preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in persistent depressive disorder, as reflected by a decrease in the HAM-D score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the HAM-D score, improvement in the patient's persistent depressive disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the HAM-D score, improvement in the patient's persistent depressive disorder preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with persistent depressive disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with persistent depressive disorder occurs within approximately 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

seasonal affective disorder

Seasonal affective disorder (SAD) is a mood disorder with a seasonal pattern, with symptoms often beginning in the fall and recurring in the spring. Many people experience feelings of sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

Patients suffering from seasonal affective disorder may have a treatment-resistant form of the disorder.

Seasonal affective disorder is characterized by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, psychomotor delay, social/emotional withdrawal, and negative thinking.

Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with seasonal affective disorder, functional connectivity changes are observed within and/or between several brain regions involved in processing, regulation, emotional memory, cognitive processes related to rumination, and impaired attention and physiological arousal. Dysfunctional connectivity is observed within and/or between the DMN, the salience network, the executive control network, and the limbic network. Functional connectivity differs significantly from that observed in healthy controls.

Treatment of patients with seasonal affective disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of seasonal affective disorder.

Improvement in seasonal affective disorder, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's seasonal affective disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in seasonal affective disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in seasonal affective disorder, as reflected by a decrease in MADRS scores, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the MADRS score, improvement in the patient's seasonal affective disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the MADRS score, improvement in seasonal affective disorder preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in seasonal affective disorder, as reflected by a decrease in HAM-D scores, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the HAM-D score, improvement in the patient's seasonal affective disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the HAM-D score, improvement in the patient's seasonal affective disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with seasonal affective disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with seasonal affective disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

bipolar disorder

Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). BD is a relapsing, chronic disorder that affects more than 1% of the global population, regardless of ethnic origin or socioeconomic status.

Patients with BD may develop treatment-resistant forms of the disorder.

BD is classified as bipolar I disorder if there is at least one manic episode, with or without depressive episodes. If there is at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode, it is classified as bipolar II disorder. If these symptoms are due to medication or medical problems, they are not diagnosed as bipolar disorder.

Typically, patients with BD, whether diagnosed with bipolar II or bipolar I disorder, are experiencing a major depressive episode, particularly during the current episode.

The severity of a current major depressive episode can be assessed using the Montgomery-Osberg Depression Rating Scale (MADRS). Patients may have a total score of 19 or higher, for example, 24 or higher, or even 37 or higher.

Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale [BDRS] total score of 19 or greater, for example, 24 or greater, particularly 37 or greater.

BD is characterized by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, psychomotor delay, social/emotional withdrawal, and negative thinking.

Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAM-D), or the Bipolar Depression Rating Scale [BDRS].

The BDRS is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated for clinical use by trained raters. Based on a clinical interview, the BDRS items assess the severity of depressive and/or mixed symptoms reported by the patient both currently and over the past few days. If there is a discrepancy between current symptoms and the past few days, the current symptoms should be factored into the assessment. This scale contains 20 items and has a maximum possible score of 60. Higher scores indicate greater severity.

These items address depressed mood; sleep disturbances; appetite disturbances; decreased social participation; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; blunted affect; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal thoughts; guilt; psychotic symptoms; irritability; anxiety; increased motor activity; increased speech activity; and agitation.

Each of these aspects is evaluated and given a score of 0, 1, 2, or 3.

Patients with BD exhibit characteristic abnormal intrinsic organization and interconnectedness of their resting-state neural networks. Compared to healthy controls, resting-state functional magnetic resonance imaging studies have revealed altered functional connectivity within and/or between specific regions of the default-mode network, the salience network, and the central executive network. Altered functional connectivity, particularly within the default-mode network, has also been observed in patients with sleep disorders.

Treatment of patients with BD, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BD.

As reflected by a decrease in CGI-S scores, improvement in BD is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD, as reflected by a decrease in MADRS score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the MADRS score, improvement in the patient's BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the MADRS score, improvement in BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD, as reflected by a decrease in the HAM-D score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the HAM-D score, improvement in the patient's BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the HAM-D score, improvement in BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD, as reflected by a decrease in the BDRS score, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in the BDRS score, improvement in the patient's BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the BDRS score, improvement in BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with BD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with BD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

anxiety disorder

Anxiety disorders are a type of mental illness. Symptoms include feelings of tension, panic, and fear, as well as sweating and a rapid heartbeat. Anxiety involves complex cognitive, affective, physiological, and behavioral response systems associated with preparing for anticipated events or situations perceived as threatening.

Anxiety disorders are also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

The severity of anxiety disorders can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Anxiety disorders are also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

Anxiety disorders are studied using functional magnetic resonance imaging. Generally, all anxiety disorders exhibit abnormalities in the default mode neural network (DMN). Additionally, the neural networks affected by these disorders include the salience network (SN) and the sensorimotor network (SMN). Compared to the DMN, the resting-state balance within and/or between these networks, such as the SMN and SN, may be abnormal in various anxiety disorders.

Treatment of patients with anxiety disorders, including treatment-resistant forms, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of anxiety.

In patients suffering from an anxiety disorder, a reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with anxiety disorders, the reduction or elimination of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with anxiety disorders, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from an anxiety disorder, including a treatment-resistant form, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from an anxiety disorder, including a treatment-resistant form, a clinical response preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with these anxiety disorders, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such anxiety disorders, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such anxiety disorders, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., at about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, at about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from anxiety disorders, including treatment-resistant forms, the reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with anxiety disorders, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with anxiety disorders, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with anxiety disorders, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The above generally applies to anxiety disorders, including anxiety disorders due to medical conditions, which occur when a medical condition causes intense fear, anxiety, or panic, as well as the specific conditions discussed in more detail below; other specified anxiety disorders, which may be diagnosed when a patient meets most but not all criteria for an anxiety disorder; and unspecified anxiety disorder, which is often diagnosed when a patient experiences anxiety or panic but lacks sufficient information to make a full diagnosis of another anxiety disorder.

Improvement in maternal functioning in patients with anxiety disorders is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with anxiety disorders occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Separation anxiety disorder is characterized by excessive anxiety about separation from home and/or people to whom the patient has a strong emotional attachment.

Separation situations can cause significant distress to individuals, and separation can make it difficult to attend school or work. Individuals with separation anxiety disorder may also experience excessive anxiety about unwelcome events that occur to important people in their lives, such as family members.

Separation anxiety disorder is also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from separation anxiety disorder may have a treatment-resistant form of the disorder.

The severity of separation anxiety disorder can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Separation anxiety disorder is also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

Separation anxiety disorder is studied using functional magnetic resonance imaging. Generally, all anxiety disorders exhibit abnormalities in the default mode neural network (DMN). Additionally, the neural networks affected by these disorders include the salience network (SN) and the sensorimotor network (SMN). Compared to the DMN, the resting-state balance within and/or between these networks, such as the SMN and SN, may be abnormal in various anxiety disorders.

Treatment of patients with separation anxiety disorder, including treatment-resistant forms, with 5-MeO-DMT or pharmaceutically acceptable salts thereof results in a reduction or elimination of anxiety.

In patients suffering from separation anxiety disorder, a reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with separation anxiety disorder, a reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with separation anxiety disorder, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from separation anxiety disorder, including the treatment-resistant form, a clinical response preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with this type of separation anxiety disorder, including the treatment-resistant form, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such separation anxiety disorder, including the treatment-resistant form, as reflected by a HAM-A score of 7 or less, the relief of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such separation anxiety disorder, including the treatment-resistant form, as reflected by a HAM-A score of 7 or less, the relief of anxiety preferably persists for at least 6 days; especially for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from separation anxiety disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with separation anxiety disorder, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with separation anxiety disorder, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with separation anxiety disorder, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within approximately 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with separation disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with separation disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Agoraphobia is a fear of situations or places that may cause panic, feelings of being trapped, helplessness, or embarrassment.

People with agoraphobia may find it difficult to leave their homes. The thought of leaving the house can trigger significant anxiety, to the point where they want to avoid it. Fear of crowds, travel, elevators, movie theaters, and shopping malls can cause significant distress.

Patients with agoraphobia may also have recurrent panic attacks.

Agoraphobia is also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from agoraphobia may have a treatment-resistant form of the disorder.

The severity of agoraphobia can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Agoraphobia has also been linked to suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

Functional magnetic resonance imaging in people with agoraphobia reveals altered functional connectivity within and/or between anxiety-related resting-state neural networks.

Treatment of patients with agoraphobia, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates anxiety.

In patients suffering from agoraphobia, a reduction or elimination of anxiety is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, a reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from agoraphobia, including treatment-resistant forms, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from agoraphobia, including treatment-resistant forms, a clinical response preferably lasts for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with agoraphobia, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such agoraphobia, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, anxiety relief occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such agoraphobia, including treatment-resistant forms, anxiety relief preferably persists for at least 6 days; especially for at least 14 days; and more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from agoraphobia, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with agoraphobia, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with agoraphobia, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with agoraphobia, including treatment-resistant forms, reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of suicidal ideation preferably lasts for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with agoraphobia is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with agoraphobia occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry about a wide range of situations and issues. People with GAD may anticipate disaster and worry excessively about money, health, family, work, or other issues.

GAD is diagnosed when an individual experiences persistent, excessive worry about everyday problems that is disproportionate to the perceived threat. People with GAD typically experience excessive fear that can persist for months or even years.

GAD interferes with social, occupational, or other important areas of functioning.

GAD is also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients with GAD may develop a treatment-resistant form of the disorder.

The severity of GAD can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

GAD is also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

GAD patients also exhibit altered functional connectivity, particularly within the default mode neural network.

Treatment of patients with GAD, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates anxiety.

In patients with GAD, a reduction or elimination of anxiety is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with GAD, the reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with GAD, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients with GAD, including treatment-resistant forms, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients with GAD, including treatment-resistant forms, a clinical response preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with such GAD, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with GAD, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients with GAD, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with GAD, including the treatment-resistant form, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14) is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients with GAD, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with GAD, including the treatment-resistant form, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with GAD, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with GAD, including the treatment-resistant form, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with GAD, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with GAD, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with GAD, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients with GAD, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of suicidal ideation preferably lasts for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with GAD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with GAD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Social anxiety disorder [SAD], also known as social phobia, is one of the most common types of anxiety.

SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations and can lead to impairment in school, work, or relationships.

SAD is also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients with SAD may develop a treatment-resistant form of the disorder.

The severity of SAD can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

SAD is also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

In SAD patients, altered functional connectivity is observed within and/or between resting-state neural networks, e.g., the default mode neural network and the salience neural network.

Treatment of patients with SAD, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates anxiety.

In patients with SAD, a reduction or elimination of anxiety is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with SAD, the reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with SAD, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from SAD, including treatment-resistant forms, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from SAD, including treatment-resistant forms, a clinical response preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with such SAD, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with such SAD, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients with such SAD, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with SAD, including the treatment-resistant form, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients with SAD, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with SAD, including the treatment-resistant form, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with SAD, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the Anxious Mood Item (Item 1) score of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with SAD, including the treatment-resistant form, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with SAD, including treatment-resistant forms, the reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with SAD, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with SAD, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with SAD, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with SAD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with SAD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Anxiety is a core feature of panic disorder . People with panic disorder experience spontaneous panic attacks, which are sudden attacks of intense fear or discomfort that peak within minutes.

Panic attacks are characterized by many somatic anxiety symptoms, including sweating, shivering, trembling, headache, heart palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

Additionally, this disorder can often be characterized by anxiety about future panic attacks. Patients may become obsessed with the fear of recurring attacks.

Panic disorder is also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from panic disorder may have a treatment-resistant form of the disorder.

The severity of panic disorder can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Panic disorder is also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

Patients with panic disorder exhibit altered functional connectivity within and/or between the default mode and sensorimotor networks.

Treatment of patients with panic disorder, including treatment-resistant forms, with 5-MeO-DMT or pharmaceutically acceptable salts thereof reduces or eliminates anxiety.

In patients suffering from panic disorder, a reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients with panic disorder, the reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with panic disorder, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from panic disorder, including the treatment-resistant form, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from panic disorder, including the treatment-resistant form, a clinical response preferably lasts for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with such panic disorder, including the treatment-resistant form, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such panic disorder, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such panic disorder, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, relief of anxiety preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1 to 6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., at about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, at about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from panic disorder, including the treatment-resistant form, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with panic disorder, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with panic disorder, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with panic disorder, including treatment-resistant forms, reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of suicidal ideation preferably lasts for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with panic disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with panic disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A phobia is an anxiety disorder defined as a persistent and excessive fear of an object or situation. Patients with a phobia experience intense anxiety when anticipating or being exposed to the feared stimulus. Phobias include animal phobias (spiders, snakes, dogs), natural environment phobias (tornadoes, heights, water, fire), blood transfusion phobias (needle phobias, medical procedures), situational phobias (flying, confined spaces), and other phobias (phobias that do not fall into the previous categories).

Phobias typically have a rapid onset and typically persist for more than six months. Patients make significant efforts to avoid the feared stimulus. The fear and avoidance cause significant distress and/or impairment in occupational, academic, or social functioning.

Phobias are also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from phobias may suffer from treatment-resistant forms of the disorder.

The severity of phobias can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Phobias are also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

In individuals with specific phobias, the amygdala, anterior cingulate cortex (ACC), and insular cortex all appear to be hypersensitive to phobia-relevant stimuli. For example, functional neuroimaging studies have shown that the dorsal part of the anterior cingulate cortex (dACC), part of the salience network, is hypersensitive to phobia-relevant stimuli or the anticipation of such stimuli.

Treatment of patients with phobias, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts results in a reduction or elimination of anxiety.

In patients suffering from phobias, a reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 1st day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and/or on the 28th day.

In patients with phobias, the reduction or elimination of anxiety occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with phobias, including treatment-resistant forms, a clinical response is reflected by a decrease in the HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from phobias, including treatment-resistant forms, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score before treatment. In patients suffering from phobias, including treatment-resistant forms, a clinical response preferably lasts for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the HAM-A score of at least 50%.

In patients with these phobias, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such phobias, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, anxiety relief occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such phobias, including treatment-resistant forms, anxiety relief preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from phobias, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from phobias, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety in patients with phobias, including treatment-resistant forms, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., at about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from phobias, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from phobias, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from phobias, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with phobias, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with phobias, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with phobias, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients with phobia is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with phobias occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Substance/drug-induced anxiety disorder is an anxiety disorder characterized by anxiety or panic attacks following the use of alcohol, drugs of abuse, or medications, or exposure to toxins. Substance/drug-induced anxiety disorder causes prominent symptoms of panic or anxiety, which may occur during the intoxication or withdrawal phase of substance or drug use.

These disturbances cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

While taking a substance or medication, or within a short time thereafter, individuals with substance/medication-induced anxiety disorder may feel tense and worried, experience symptoms of negative thinking, have trouble concentrating or remembering things, have fears of losing control or going crazy or dying, have gastrointestinal problems that can cause weight loss, and have chills, hot flashes, sweating, tremors, numbness or a racing heart, difficulty breathing, difficulty swallowing, or chest pain.

Substance/medication-induced anxiety disorder also involves one or more of the following: sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

The severity of substance-induced anxiety disorder can be assessed using the Beck Anxiety Inventory (BAI). It can also be assessed using the Hamilton Anxiety Rating Scale (HAM-A); the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14); the HAM-A Anxious Mood item (item 1); and the Brief Mental State Rating Scale (BPRS) item "Anxiety."

Substance/drug-induced anxiety disorder is also associated with suicidal thoughts.

Suicidal ideation can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS).

Functional magnetic resonance imaging in individuals with substance/drug-induced anxiety disorder reveals altered functional connectivity within and/or between anxiety-related resting-state neural networks.

Treatment of patients with substance/drug-induced anxiety disorders, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts results in a reduction or elimination of anxiety.

In patients suffering from substance/drug induced anxiety disorder, a reduction or elimination of anxiety is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorder, the reduction or elimination of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 6 days, particularly for at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with substance/drug-induced anxiety disorder, including treatment-resistant forms, a clinical response is reflected by a decrease in HAM-A score of at least 50% relative to the pretreatment score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28, respectively.

In patients suffering from substance/drug induced anxiety disorder, including treatment-resistant forms, as reflected by at least a 50% decrease in the HAM-A score compared to the respective pre-treatment scores, a clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from substance/drug induced anxiety disorder, including treatment-resistant forms, as reflected by at least a 50% decrease in the HAM-A score, a clinical response preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from these substance/drug induced anxiety disorders, including treatment-resistant forms, relief of anxiety is reflected by a HAM-A score of 7 or less at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from such substance/drug induced anxiety disorder, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, the relief of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from such substance/drug induced anxiety disorder, including treatment-resistant forms, as reflected by a HAM-A score of 7 or less, the relief of anxiety preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorder, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the HAM-A anxiety subscale score (sum of items 1-6 and 14), is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

In patients suffering from substance/drug-induced anxiety disorder, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the mental anxiety subscale score of the HAM-A (sum of items 1-6 and 14), preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorder, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorder, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood Item (Item 1) of the HAM-A, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorders, including treatment-resistant forms, a reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, is observed at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients suffering from substance/drug-induced anxiety disorders, including treatment-resistant forms, the reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the BPRS item 'Anxiety' score, preferably persists for at least 6 days; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients with substance/drug-induced anxiety disorders, including treatment-resistant forms, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

In patients with substance/drug-induced anxiety disorders, including treatment-resistant forms, a reduction or elimination of suicidal ideation is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In patients with substance-induced anxiety disorders, including treatment-resistant forms, a reduction or elimination of suicidal ideation occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation preferably persists for at least 6 days, particularly at least 14 days, and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients with drug/medication-induced anxiety disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with substance/medication-induced anxiety disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

somatic symptom disorder

Somatic symptom disorder is a mental disorder diagnosed when a person is significantly preoccupied with physical symptoms, such as pain, weakness, or shortness of breath, that cause significant distress and/or functional impairment and/or interfere with daily life. The emotions and behaviors associated with the disorder are excessive or severe.

Health-related quality of life is often impaired both physically and mentally. In severe somatic symptom disorders, the impairment is significant and, if persistent, can lead to disability.

Somatic symptom disorder involves one or more of the following: sleep disturbances, cognitive dysfunction, and anxiety.

Brain functional connectivity analysis reveals alterations within and/or between resting-state neural networks in patients with somatic symptom disorder compared to healthy controls. Alterations are identified within and/or between the default mode network (DMN), the salience network, the dorsal attention network (DAN), and the sensorimotor network. Somatic symptom disorder may be associated with altered sensory-discriminative processing of somatic symptoms, which is influenced by emotional processing.

Treatment of patients suffering from somatic symptom disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the somatic symptom disorder.

Improvement in somatic symptom impairment, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's somatic symptom disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in somatic symptom disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with somatic symptom disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with somatic symptom disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Obsessive-Compulsive and Related Disorders

Obsessive Compulsive Disorder (OCD) is a mental illness characterized by recurring unwanted thoughts or sensations (obsessions) or repetitive impulses to perform certain actions (compulsions). Patients may experience both obsessions and compulsions.

Patients with OCD may have a treatment-resistant form of the disorder.

OCD involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Neuroimaging studies using functional magnetic resonance imaging in patients with OCD have shown altered functional connectivity within and/or between the frontoparietal, salience, and default mode networks. Altered functional connectivity in these affected networks, particularly the default mode network, has also been associated with sleep disturbances.

Treatment of patients with OCD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of OCD.

Improvement in OCD, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's OCD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in OCD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with OCD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with OCD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

People with body dysmorphic disorder (BDD) have a misperception of flaws in their appearance that interfere with their ability to function in daily life and cause them anxiety-provoking obsessions, ritualistic behaviors, and emotional distress.

Patients with BDD may have a treatment-resistant form of the disorder.

BDD involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Functional magnetic resonance imaging (FMR) of patients with BDD reveals alterations within and/or between specific brain regions located in the default mode network, dorsal attention network, and salience network. Altered functional connectivity within these affected networks, particularly the default mode network, has also been associated with sleep disturbances.

Treatment of patients with BDD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BDD.

Improvement in BDD, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's BDD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in BDD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with BDD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with BDD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Post-traumatic stress disorder [PTSD]

Post-traumatic stress disorder (PTSD) is a mental health condition that can develop after experiencing or witnessing a terrifying event. Symptoms can include flashbacks, nightmares, severe anxiety, and uncontrollable thoughts about the event.

Patients with PTSD may develop a treatment-resistant form of the disorder.

PTSD is accompanied by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Analysis of resting-state functional magnetic resonance images of patients with PTSD shows alterations within and/or between regions located in the default mode and salience networks.

Treatment of patients with PTSD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of PTSD.

Improvement in PTSD, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's PTSD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in PTSD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients with PTSD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by the improvement in the BIMF total score, the improvement in maternal function in patients with PTSD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by the improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

pain disorders

Sleep disturbances occur in patients with pain and are associated with chronic pain .

Chronic pain, also referred to as persistent pain, is persistent pain that persists beyond the normal recovery period, for example, after an injury or surgery, despite medication or treatment. Patients can also experience chronic pain without any apparent cause, such as a history of injury or surgery.

Chronic pain is accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Patients with chronic pain exhibit brain alterations related to brain function and structure. These alterations are associated with the persistence of pain long after the initial nociceptive input has subsided. Resting-state functional magnetic resonance imaging (fMRI) reveals alterations in distinct regions within and/or between the default mode neural network, the motor/sensorimotor neural network, and the salience neural network.

Treatment of patients with chronic pain, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of chronic pain.

As reflected by a decrease in CGI-S scores, improvement in chronic pain is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's chronic pain occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in chronic pain preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with chronic pain is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with chronic pain occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Fibromyalgia is a chronic condition characterized by widespread musculoskeletal pain, often spread throughout the body or in multiple areas, accompanied by fatigue, sleep disturbances, memory, and mood issues. Patients may also experience muscle and joint stiffness, tenderness, numbness or tingling in the arms and legs, problems with concentration, clear thinking, and memory (sometimes referred to as "fibro fog"), increased sensitivity to light, noise, smells, and temperature, or digestive problems such as bloating or constipation.

Studies show that people with fibromyalgia have a heightened sensitivity to pain, feeling pain even when others do not.

Fibromyalgia is associated with one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Brain imaging studies and other investigations have found evidence of altered signaling in the neural pathways that transmit and receive pain in people with fibromyalgia. These changes may also contribute to the fatigue, sleep disturbances, and cognitive problems experienced by many people with the disorder.

Resting-state functional magnetic resonance imaging of patients with fibromyalgia shows altered functional connectivity within and/or between the DMN and executive attention networks, and between the DMN and the insular cortex, a brain region known to process evoked pain.

Treatment of patients with fibromyalgia, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of fibromyalgia.

As reflected by a decrease in the CGI-S score, improvement in fibromyalgia is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's fibromyalgia occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in fibromyalgia preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with fibromyalgia is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with fibromyalgia occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Migraines are severe, throbbing pains that can feel like a pounding or pulsating sensation, usually on one side of the head. They are often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last from hours to days, and the pain can be so severe that it interferes with daily life.

In some patients, symptoms known as aura occur before or along with the headache. These symptoms may include visual disturbances, such as flashes of light or blind spots, or other disturbances, such as tingling on one side of the face or in the arms or legs, and difficulty speaking.

Migraines are accompanied by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Headache disorders are associated with atypical functional connectivity within and/or between multiple core resting-state neural networks, including the salience and default mode networks, as well as atypical functional connectivity in regions associated with pain processing.

In patients with migraine, resting-state neural network analysis reveals differences compared to healthy controls. Studies during migraine attacks reveal marked abnormalities in neural networks involved in mediating the cognitive, attentional, somatosensory, and emotional components of pain.

Treatment of patients suffering from migraine, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of migraine.

As reflected by a decrease in CGI-S scores, improvement in migraine is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's migraine occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the migraine preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with migraine is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with migraine occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Mental and behavioral disorders caused by the use of psychoactive substances

Sleep disturbances occur in patients with certain mental and behavioral disorders due to the use of psychoactive substances.

Substance use disorder (SUD) is a mental disorder that affects a person's behavior, causing them to lose control over their use of substances, such as legal or illegal drugs, alcohol, or medications. Symptoms can range from moderate to severe, with addiction being the most severe form of SUD.

Substance use disorders involve one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

Resting-state functional connectivity (rsFC) has been found to be altered not only in patients with sleep disorders but also in patients with substance use disorders. Specifically, cognitive control deficits have been associated with altered connectivity within and/or between resting-state neural networks, such as the default mode network, the salience network, the central executive network, the limbic network, and the reward network.

Treatment of patients with substance use disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the substance use disorder.

Improvement in drug use disorder, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's substance use disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the patient's substance use disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with substance use disorders is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with a substance use disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

psychotic disorder

Psychotic disorders are serious mental disorders characterized by abnormal thinking and cognition. They are characterized by significant impairment in reality testing and behavioral alterations, manifested by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking (typically manifested as disorganized speech), extremely disorganized behavior, and experiences of passivity and control. Negative symptoms include blunted or indifferent affect and apathy, and altered behavior manifested by psychomotor disturbances.

Patients with psychotic disorders may develop treatment-resistant forms of the disorder.

Psychotic disorders involve one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

Functional magnetic resonance imaging of the resting-state neural network in patients with psychosis reveals significant alterations in distinct regions within and/or between the central executive network, default mode network, and salience network. Alterations in the resting-state neural network can also be identified in patients at risk for psychosis.

Treatment of patients suffering from psychotic disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the psychotic disorder.

Improvement in psychotic disorder, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's psychotic disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the psychotic disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with psychotic disorders is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with a psychotic disorder occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

schizophrenia

Schizophrenia is a severe mental health condition characterized by disturbances in multiple mental modalities, including thought, perception, self-experience, cognition, will, emotion, and behavior. Psychomotor disturbances, including catatonia, may also be present.

Patients with schizophrenia may develop treatment-resistant forms of the disorder.

Schizophrenia is characterized by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

In particular, abnormal resting-state functional connectivity within and/or between the default mode network, frontoparietal network, and salience network has been reported in individuals with schizophrenia. In individuals at high risk for psychosis and those diagnosed with schizophrenia, several studies have found an association between sleep disturbances and symptom severity.

Treatment of patients with schizophrenia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the schizophrenia.

Improvement in schizophrenia, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's schizophrenia occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in schizophrenia preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with schizophrenia is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with schizophrenia occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

eating disorders

An eating disorder is a mental disorder characterized by abnormal eating behaviors that negatively affect a person's physical or mental health.

Patients suffering from eating disorders may suffer from treatment-resistant forms of the disorder.

Eating disorders are accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

In patients with eating disorders, findings from functional neural network connectivity studies indicate disruptions in resting-state connectivity within and/or between the executive network, default mode network, and salience network.

Treatment of patients with eating disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the eating disorder.

Improvement in eating disorders, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's eating disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the eating disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with eating disorders is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with eating disorders occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Attention Deficit Hyperactivity Disorder (ADHD)

Attention-deficit hyperactivity disorder (ADHD) is a medical condition that affects a person's behavior. People with ADHD may appear anxious, have difficulty concentrating, and act impulsively.

ADHD involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state neural network analysis in patients with ADHD reveals dysfunctional connectivity across multiple brain resting-state networks, particularly within and/or between distinct regions of the default mode network, dorsal attention network, and salience network.

Treatment of patients with ADHD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of ADHD.

Improvement in ADHD, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's ADHD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in ADHD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with ADHD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by the improvement in the BIMF total score, the improvement in maternal function in patients with ADHD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by the improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

personality disorder

Schizotypal personality disorder is a psychiatric condition characterized by a consistent pattern of intense discomfort with relationships and social interactions. Patients with schizotypal personality disorder exhibit unusual thoughts, speech, and behaviors, which interfere with their ability to form and maintain relationships.

Patients with schizotypal personality disorder may have a treatment-resistant form of the disorder.

Schizotypal personality disorder involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

In patients with schizotypal personality disorder, functional connectivity of the DMN, particularly related to cognitive and emotional regulation, is altered. Neuroimaging analysis using fMRI further reveals alterations within and/or between the frontoparietal and dorsal attention networks.

Treatment of patients with schizotypal personality disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the schizotypal personality disorder.

Improvement in schizotypal personality disorder, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's schizotypal personality disorder occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the patient's schizotypal personality disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients with schizotypal personality disorder is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with schizotypal personality disorder occurs within approximately 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Persistent mood instability, impulsivity, psychosomatic disturbances, and interpersonal dysfunction are characteristic features of borderline personality disorder (BPD).

Patients with BPD may develop a treatment-resistant form of the disorder.

BPD involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Patients with borderline personality disorder exhibit abnormal connectivity patterns in their resting-state neural networks. Analysis of functional connectivity in resting-state neural networks using functional magnetic resonance imaging reveals alterations within and/or between various neural networks, such as the default mode network and the salience network.

Treatment of patients with BPD, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BPD.

Improvement in BPD, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's BPD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in BPD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with BPD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with BPD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Autism Spectrum Disorder (ASD)

Individuals with autism spectrum disorder (ASD), including autism, Asperger's syndrome, and atypical autism, have persistent deficits in the ability to initiate and maintain reciprocal social interactions and social communication. These conditions are also characterized by a range of restricted, repetitive, and inflexible behaviors, interests, or activities that are clearly atypical or excessive for the individual's age and sociocultural context.

This disorder begins during development, but symptoms may not fully manifest until later. The impairments are severe enough to affect the patient's ability to function in personal, family, social, educational, occupational, or other areas.

ASD involves one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, and social/emotional withdrawal.

ASD as a disturbance of brain neural network connectivity. Neuroimaging studies have shown that ASD is associated with significant alterations in brain neural networks, including abnormal responses in specific brain regions, altered functional connectivity within and/or between the default mode network (DMN) and sensory processing networks, and disruption of neural synchronization between brain regions.

Treatment of patients with ASD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of ASD.

As reflected by a decrease in CGI-S scores, improvement in ASD is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's ASD occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in ASD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with ASD is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with ASD occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

chronic fatigue syndrome

Fatigue is a feeling of exhaustion, weakness, and decreased energy. It is experienced as a weakening or depletion of physical or mental resources. While fatigue is considered normal after a period of mental or physical exertion, it can also occur as a symptom of a medical condition in the absence of such exertion.

Chronic fatigue worsened by activity is a prominent symptom of chronic fatigue syndrome. In this disorder, severe fatigue is accompanied by neurocognitive, autonomic, and immunological symptoms.

It has been reported that various abnormalities in normal sleep patterns may act as perpetuating factors in patients with chronic fatigue syndrome.

In the early stages of the disease, patients with chronic fatigue syndrome tend to complain of hypersomnia. This is often followed by a general decrease in sleep efficiency as the disease progresses to a more chronic stage. Even if patients sleep for a considerable amount of time, they tend to feel unrefreshed upon waking.

Compensatory behaviors for non-restorative nighttime sleep can lead to alterations in circadian rhythms. Vivid dreams, periodic limb movements during sleep, and restless legs syndrome are also frequently reported.

Chronic fatigue syndrome is characterized by one or more of the following symptoms: sleep disturbances, cognitive dysfunction, and anxiety.

Patients with chronic fatigue syndrome exhibit abnormal resting-state functional connectivity, which significantly correlates with the severity of their chronic fatigue. The involved neural networks are also involved in sleep regulation.

Treatment of patients suffering from chronic fatigue syndrome, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of chronic fatigue syndrome.

Improvement in chronic fatigue syndrome, as reflected by a decrease in CGI-S scores, is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's chronic fatigue syndrome occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the patient's chronic fatigue syndrome preferably persists for at least 6 days; particularly for at least 14 days; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with chronic fatigue syndrome is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with chronic fatigue syndrome occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Medical health conditions that cause associated mental or neurological conditions

Patients with traumatic brain injury

Traumatic brain injury (TBI) is damage to the brain caused by an external force.

Traumatic brain injury is characterized as primary or secondary. Primary brain injury refers to structural damage caused during the impact, such as from contact, acceleration-deceleration, and/or rotational forces. Secondary brain injury refers to damage sustained by subsequent cellular processes resulting from the primary injury (i.e., hypoxia and/or increased intracranial pressure).

TBI can cause one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state functional connectivity analyses reveal alterations in overall functional connectivity within and/or between resting-state neural networks, such as the DMN, frontoparietal network, executive network, and sensorimotor network. For example, highly connected regions within the DMN are particularly vulnerable to alterations in functional connectivity following traumatic brain injury.

Treatment of patients with TBI, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of TBI.

As reflected by a decrease in CGI-S scores, improvement in TBI is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's TBI occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the TBI preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with TBI is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with TBI occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Patients with HIV infection

HIV disease is caused by infection with the human immunodeficiency virus type-1 (HIV-1). Even with concurrent antiretroviral therapy, HIV-infected patients develop neurological symptoms.

HIV causes one or more of the following symptoms: sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state functional connectivity analyses in patients with neurocognitive impairment due to HIV infection reveal impaired functional connectivity within and/or between specific regions of the default mode, salience, and executive networks.

Treatment of patients with HIV, including those with treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of HIV.

As reflected by a decrease in the CGI-S score, improvement in HIV is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's HIV status occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in HIV status preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with HIV is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with HIV occurs within approximately 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Patients with post-COVID morbidity

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Post-COVID illness (sometimes referred to as “long COVID”) is a systemic condition that often involves severe symptoms following infection with SARS-CoV-2. It is an often debilitating illness that occurs in at least 10% of infections.

The World Health Organization (WHO) defines this condition as an unexplained syndrome that develops within three months of infection, lasts at least two months, may fluctuate, and is not due to an alternative diagnosis.

Post-COVID morbidity can include a wide range of persistent health problems that can last for weeks, months, or years, and sometimes result in disability.

Individuals with post-COVID-19 symptoms most commonly report typical symptoms such as fatigue, shortness of breath, and cognitive impairment, such as difficulty thinking or concentrating (sometimes referred to as "brain fog"). However, patients may also experience respiratory and cardiac symptoms, neurological symptoms, such as sleep problems (e.g., insomnia), and digestive symptoms.

Patients with post-COVID-19 often experience residual symptoms, such as anxiety, even after surviving mild illness. Anxiety in post-COVID-19 can be a direct result of SARS-CoV-2 infection or stem from acute SARS-CoV-2 infection-related hospitalization, particularly admission to an intensive care unit.

Individuals suffering from post-COVID-19 post-traumatic stress disorder (PTSD) often experience fears about their health and recovery, stress about losing their jobs and the financial impact, and worry about their family and friends also contracting the disease. Furthermore, post-COVID-19 post-traumatic stress disorder (PTSD) can cause sleep disturbances, difficulty concentrating, memory problems, mood swings, flashbacks, breathing difficulties, chest pain, and racing thoughts.

Post-COVID morbidity involves one or more of the following: sleep disturbances, cognitive dysfunction, and anxiety.

Functional magnetic resonance imaging (FU) of patients with post-COVID-19 disease reveals alterations within and/or between resting-state neural networks. Most commonly, the default-mode neural network is affected.

Treatment of patients with post-COVID morbidity, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of post-COVID morbidity.

As reflected by a decrease in CGI-S scores, improvement in post-COVID-19 disease status is observed approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., approximately 24 hours; on day 7; on day 14; and/or on day 28.

As reflected by a decrease in the CGI-S score, improvement in the patient's post-COVID condition occurs within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by a decrease in the CGI-S score, improvement in the post-COVID condition preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with post-COVID-19 disease is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by the improvement in the BIMF total score, the improvement in maternal function in patients with post-COVID-19 disease occurs within approximately 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by the improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

idiopathic sleep disorder

Treatment of patients with idiopathic sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the idiopathic sleep disorders.

A reduction or elimination of idiopathic sleep disturbances is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

The reduction or elimination of the idiopathic sleep disorder preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of the idiopathic sleep disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In one embodiment, the reduction or elimination of idiopathic sleep disturbance is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, more preferably for at least 28 days.

In cases of idiopathic sleep disorders, clinical response can be reflected by a decrease in the Clinical Global Impression-Severity Scale (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease of at least 1 point. Preferably, the CGI-S decreases by at least 2 points and/or to 0 points. A decrease of at least 3 points and/or to 0 points is particularly preferred.

Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S scores, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

As reflected by a decrease in CGI-S scores, improvement in idiopathic sleep disorders occurs within approximately 24 hours after the last dose of 5-MeO-DMT or its pharmaceutically acceptable salt.

As reflected by a decrease in the CGI-S score, improvement in idiopathic sleep disorder preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In one embodiment, improvement in idiopathic sleep disorder, as reflected by a decrease in CGI-S score, is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, more preferably for at least 28 days.

For idiopathic sleep disorders, improvement in sleep disorder, as reflected by a score of at least 'very improved' on the Clinical Global Impression-Improvement [CGI-I] score or the Patient Global Impression-Improvement [PGI-I] score, is observed on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and/or on day 28.

Improvement in idiopathic sleep disorders, as reflected by a score of at least 'very improved' on the CGI-I or PGI-I score, preferably occurs within about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sleep disturbance, as reflected by a score of at least 'very improved' on the CGI-I score or PGI-I score, preferably persists for at least 6 days; especially for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In one embodiment, improvement in the idiopathic sleep disorder, as reflected by a score of at least 'very improved' on the CGI-I score or PGI-I score, is observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, more preferably for at least 28 days.

Improvement in cases of idiopathic sleep disorders may also be assessed by any other measure reflecting changes in sleep quality or quantity, such as the Pittsburgh Sleep Quality Index (PSQI), as indicated above.

When treatment outcome is assessed using the PSQI, treatment success is indicated by (i) a decrease in the overall score, preferably (ii) a decrease to 5 or less. The applied recall period begins no earlier than the time when the acute hallucinatory experience has subsided after the last administration.

Improvement in idiopathic sleep disorders, as reflected by a decrease in the PSQI overall score, particularly a decrease to 5 or less, preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

This improvement in idiopathic sleep disorder, as reflected by a decrease in the PSQI overall score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in idiopathic sleep disturbance, as reflected by a decrease in PSQI overall score, particularly a decrease to 5 or less, is observed as early as day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; day 7; day 14; and/or day 28.

In one embodiment, improvement in idiopathic sleep disturbance, as reflected by a decrease in PSQI overall score, particularly a decrease to 5 or less, is observed at day 7 and preferably persists until day 14, more preferably until day 28.

Improvement in maternal function in patients with sleep disorders is reflected by an improvement in the BIMF total score at least on day 7; day 14; and/or day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As reflected by an improvement in the BIMF total score, improvement in maternal function in patients with sleep disorders occurs within approximately 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. As reflected by an improvement in the BIMF total score, improvement in maternal function preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Additional treatment modalities

Specific aspects of treatment for major depressive disorder are summarized below.

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient diagnosed with major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous route, and the patient is a lactating mother who has been advised to discontinue breastfeeding for 48 hours, e.g., 24 hours, preferably 6 hours, more preferably 3 hours, most preferably 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1, wherein the disorder is diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1 or 2, wherein the patient suffers from moderate or severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 17 or greater.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 3, wherein the patient suffers from severe major depressive disorder as indicated by a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of major depressive disorder.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 5, wherein the patient additionally suffers from suicidal ideation.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 6, wherein the patient suffers from suicidal ideation with intent to act.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 7, wherein the patient is at imminent risk of suicide.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 8, wherein the 5-MeO-DMT or salt thereof is administered in a dose or dosage regimen that causes the patient to experience a peak hallucinogenic experience.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 9, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 9, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 10, wherein 5-MeO-DMT or a salt thereof is administered in a first dose for a first administration; and 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration, unless the patient experiences a peak hallucinatory experience.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 10 or 12, wherein 5-MeO-DMT is administered in a dosage of about 0.5 mg to about 1.5 mg for a first administration, and then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiment 13, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 12 to 14, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 2 to 4 hours.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 9 to 15, wherein the occurrence of a peak hallucinatory experience is identified by achievement of at least 60% of the maximum possible score on each of the four subscales (Mystery, Positive Mood, Transcendence of Time and Space, and Ineffable) of the 30-item Revised Mystical Experiences Questionnaire [MEQ30], or by achievement of at least 60% of the maximum possible score on the Oceanic Boundless [OBN] dimension of the Altered States of Consciousness [ASC] questionnaire, or by achievement of a Peak Hallucinatory Experiences Questionnaire [PPEQ] total score of at least 75.

17. As 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 16, the occurrence of a peak hallucinatory experience is identified by the achievement of a Peak Hallucination Experience Questionnaire [PPEQ] total score of at least 75.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in any of the preceding embodiments, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 18, wherein the clinical response reflected by a decrease in the Clinical Global Impression-Severity Inventory [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 19, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 20, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score persists for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 21, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 22, wherein the clinical response occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by at least a 50% improvement in MADRS or HAM-D score compared to the respective score prior to treatment.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 23, wherein remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

25. In any one of aspects 1 to 24, a clinical response, as assessed by a 50% improvement in MADRS or HAM-D score compared to the respective score before treatment, lasting at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 25, wherein clinical response is present on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as assessed by at least a 75% improvement in MADRS or HAM-D score compared to the respective score prior to treatment.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 26, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 27, wherein the clinical response, as assessed by at least a 50% improvement in MADRS or HAM-D score compared to the respective score prior to treatment, lasts for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 28, wherein clinical response is present on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as assessed by at least a 75% improvement in MADRS or HAM-D score compared to the respective score prior to treatment.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 29, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 30, wherein the clinical response, as assessed by at least a 50% improvement in MADRS or HAM-D score compared to the respective score prior to treatment, lasts for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 31, wherein clinical response is present on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as assessed by at least a 75% improvement in MADRS or HAM-D score compared to the respective score prior to treatment.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 32, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein the patient is a lactating mother who is advised to discontinue breastfeeding for at least 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 38, wherein the treatment improves maternal function.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 39, wherein the improvement is directed to one or more, and particularly two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, maternal psychosocial well-being, social support, management, and adaptation.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 39 or 40, wherein the BIMF score is improved by at least 10%, preferably at least 20%.

Specific aspects of treatment for bipolar disorder are listed below.

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient diagnosed with bipolar disorder, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous route, and the patient is a lactating mother who is advised to discontinue breastfeeding for 48 hours, e.g., 24 hours, preferably 6 hours, more preferably 3 hours, most preferably 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1, wherein the patient is diagnosed with bipolar II disorder.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1, wherein the patient is diagnosed with bipolar I disorder.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 3, wherein the patient is currently suffering from a major depressive episode.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 4, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 19 or more, such as 24 or more, particularly 37 or more.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 4 or aspect 5, wherein the patient has a Bipolar Depression Rating Scale [BDRS] total score of 19 or greater, such as 24 or greater, in particular 37 or greater.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 6, wherein the patient has not shown adequate improvement after at least two adequate courses of therapy.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 6, wherein the patient has not had adequate improvement after at least two adequate courses of therapy, at least one of which was drug therapy.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 6, wherein the patient has not had adequate improvement after at least two adequate courses of drug therapy.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 9, wherein the patient has a Young Manic Rating Scale (YMRS) total score of 8 or less.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein 5-MeO-DMT or a salt thereof is administered in a dose or dosage regimen that allows the patient to experience the highest hallucinatory experience in aspects 1 to 10.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 11, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 11, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 11, wherein a dosage of about 1 mg; or about 2 mg; or about 3 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 12, wherein 5-MeO-DMT or a salt thereof is administered in a first dose for a first administration; and 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration, unless the patient experiences a peak hallucinatory experience.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 12 or 15, wherein 5-MeO-DMT is administered in a dosage of about 1 mg to about 3 mg for a first administration, and then increased to a dosage of about 4 mg to about 6 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and then increased to a dosage of about 7 mg to about 9 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiment 16, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 12 or 15, wherein 5-MeO-DMT is administered in a dosage of about 0.5 mg to about 1.5 mg for a first administration, and then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiment 18, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 15 to 19, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in Aspects 11 to 20, wherein the occurrence of a peak hallucinatory experience is identified by achievement of at least 60% of the maximum possible score on each of the four subscales (Mystery, Positive Mood, Transcendence of Time and Space, and Ineffable) of the 30-item Revised Mystical Experiences Questionnaire [MEQ30], or by achievement of at least 60% of the maximum possible score on the Oceanic Boundlessness [OBN] dimension of the Altered States of Consciousness [ASC] questionnaire, or by achievement of a Peak Experience Scale [PES] total score of at least 75.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 21, wherein the occurrence of a peak hallucinatory experience is identified by the achievement of a Peak Experience Scale [PES] total score of at least 75.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in any of the preceding embodiments, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 23, wherein the clinical response reflected by a decrease in the Clinical Global Impression-Severity Index [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 24, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score is observed on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 25, wherein the clinical response reflected by a decrease in the Clinical Global Impression-Severity Index [CGI-S] score persists for at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 26, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score persists for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 27, wherein the clinical response reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 28, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS, or HAM-D score compared to the respective scores prior to treatment, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 29, wherein remission of depressive symptoms as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less; or a HAM-D score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. As used in embodiments 1 to 30, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a clinical response, as reflected by at least a 50% improvement in BDRS, MADRS or HAM-D score compared to the respective scores before treatment, is observed on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 31, wherein remission of depressive symptoms as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less; or a HAM-D score of 7 or less is observed about 1 day, for example, about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 32, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS, or HAM-D score compared to the respective scores before treatment, lasts for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 33, wherein a clinical response, as reflected by at least a 75% improvement in BDRS, MADRS, or HAM-D score compared to the respective scores prior to treatment, is present on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 34, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 35, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS, MADRS or HAM-D score compared to the respective scores before treatment, lasts for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 36, wherein a clinical response is present as reflected by at least a 75% improvement in BDRS; MADRS or HAM-D score compared to the respective score prior to treatment on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 37, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 38, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS, or HAM-D score compared to the respective scores prior to treatment, lasts for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 39, wherein a clinical response is present as reflected by at least a 75% improvement in BDRS; MADRS or HAM-D score compared to the respective score prior to treatment on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 40, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less; or a HAM-D score of 7 or less on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 41, wherein the patient does not experience treatment-induced mania or hypomania.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 42, wherein the patient has a Young Manic Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, as assessed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, as assessed on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 44, wherein the patient has a Young Manic Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, as assessed on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

46. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 45, wherein the patient has a Young Manic Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, as assessed on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 46, wherein the patient has a Young Manic Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, as assessed on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 47, wherein the treatment results in improvement of at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social/emotional withdrawal or isolation.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 48, wherein the patient suffers from a sleep disorder, and the treatment reduces or eliminates the sleep disorder.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the patient suffers from insomnia, and the treatment reduces or eliminates the insomnia.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the patient suffers from hypersomnia, and the treatment reduces or eliminates the hypersomnia.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 49 to 51, wherein the reduction or elimination of sleep disturbance is reflected by an improvement in the score of the BDRS item sleep disturbance at least on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 49 to 52, wherein the reduction or elimination of sleep disturbance is reflected by an improvement in the score of the BDRS item sleep disturbance at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 49 to 53, wherein the reduction or elimination of sleep disturbance is reflected by an improvement in the score of at least the BDRS item sleep disturbance on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 49 to 54, wherein the reduction or elimination of sleep disturbance is reflected by an improvement in the score of at least the BDRS item sleep disturbance on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

56. As used in aspect 49, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a reduction or elimination of sleep disturbance as reflected by an improvement in the BDRS sleep disturbance score occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

57. As 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 56, the reduction or elimination of sleep disturbance as reflected by an improvement in the BDRS item sleep disturbance score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 56, wherein the reduction or elimination of sleep disturbance as reflected by an improvement in the BDRS sleep disturbance score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 56, wherein the reduction or elimination of sleep disturbance as reflected by an improvement in the BDRS sleep disturbance score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance is reflected by an improvement in the score of the MADRS item Reduced Sleep at least on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49 or 60, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance is reflected by an improvement in the score of at least the MADRS item Reduced Sleep on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, 60 or 61, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance is reflected by an improvement in the score of at least the MADRS item Reduced Sleep on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49 or 60 to 62, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance is reflected by an improvement in the score of at least the MADRS item Reduced Sleep on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score of the MADRS item reduced sleep occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 64, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score of the MADRS item reduced sleep persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 64, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score of the MADRS item reduced sleep persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 64, wherein the sleep disturbance is reduced sleep, and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score of the MADRS item reduced sleep persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the patient suffers from a sleep disorder, and improvement in the sleep disorder is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49 or 68, wherein the patient suffers from sleep disturbance, and improvement in sleep disturbance is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, 68 or 69, wherein the patient suffers from sleep disturbance, and improvement in sleep disturbance is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49 or 68 to 70, wherein the patient suffers from sleep disorder, and improvement in sleep disorder is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 48, wherein the patient suffers from a sleep disorder, and improvement in the sleep disorder, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 72, wherein the improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 72, wherein the improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 72, wherein the improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 48, wherein the patient suffers from a sleep disorder, wherein a reduction or elimination of the sleep disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 48 or 76, wherein the patient suffers from a sleep disorder, wherein a reduction or elimination of the sleep disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 48, 76 or 77, wherein the patient suffers from a sleep disorder, wherein a reduction or elimination of the sleep disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 48 or 76 to 78, wherein the patient suffers from a sleep disorder, wherein a reduction or elimination of the sleep disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 49, wherein the patient suffers from a sleep disturbance, and wherein a reduction or elimination of the sleep disturbance as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period extends from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 80, wherein the patient suffers from a sleep disturbance, and wherein the reduction or elimination of the sleep disturbance as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period extends from the time when the acute hallucinatory experience subsides after the last administration to the time of assessment.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 80, wherein the patient suffers from a sleep disturbance, and wherein the reduction or elimination of the sleep disturbance as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period extends from the time when the acute hallucinatory experience subsides after the last administration to the time of assessment.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 80, wherein the patient suffers from a sleep disturbance, and the reduction or elimination of the sleep disturbance as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time when the acute hallucinatory experience subsides after the last administration to the time of assessment.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 83, wherein the patient suffers from psychomotor retardation, and the treatment reduces or eliminates the psychomotor retardation.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, wherein the treatment improves or eliminates reduced energy and activity and/or reduced motivation.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 85, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of the BDRS items Reduced Energy and Activity and/or Reduced Motivation at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 84 to 86, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of the BDRS items Reduced Energy and Activity and/or Reduced Motivation at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 84 to 87, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the scores of the BDRS items Reduced Energy and Activity and/or Reduced Motivation at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 84 to 88, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the scores of at least the BDRS items Reduced Energy and Activity and/or Reduced Motivation on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 84 to 89, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the scores of at least the BDRS items Reduced Energy and Activity and/or Reduced Motivation on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 85, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the scores of the BDRS items Reduced Energy and Activity and/or Reduced Motivation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 91, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the scores of the BDRS items Reduced Energy and Activity and/or Reduced Motivation persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 91, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the scores of the BDRS items Reduced Energy and Activity and/or Reduced Motivation persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 91, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the scores of the BDRS items Reduced Energy and Activity and/or Reduced Motivation persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of at least the MADRS item malaise at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 95, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of the MADRS item malaise at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, 95 or 96, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of at least the MADRS item malaise on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 95 to 97, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of at least the MADRS item malaise on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 95 to 98, wherein the reduction or elimination of psychomotor retardation is reflected by an improvement in the score of at least the MADRS item malaise on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, wherein a reduction or elimination of psychomotor retardation as reflected by an improvement in the score of the MADRS item boredom occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 100, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the MADRS item boredom score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 100, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the MADRS item boredom score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 100, wherein the reduction or elimination of psychomotor retardation as reflected by an improvement in the MADRS item boredom score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, wherein the patient suffers from psychomotor retardation, and improvement in psychomotor retardation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 104, wherein the patient suffers from psychomotor retardation, and improvement in psychomotor retardation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84, 104 or 105, wherein the patient suffers from psychomotor retardation, and improvement in psychomotor retardation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 104 to 106, wherein the patient suffers from psychomotor retardation, and improvement in psychomotor retardation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 84 or 104 to 107, wherein the patient suffers from psychomotor retardation, and improvement in psychomotor retardation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 83, wherein the patient suffers from psychomotor retardation, and wherein improvement in psychomotor retardation as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 109, wherein the improvement in psychomotor retardation as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score persists for at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 109, wherein the improvement in psychomotor retardation as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score persists for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 109, wherein the improvement in psychomotor retardation as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score persists for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 112, wherein the patient suffers from negative thinking, and the treatment reduces or eliminates the negative thinking.

114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, wherein the treatment reduces or eliminates feelings of worthlessness; feelings of helplessness and hopelessness; and/or feelings of guilt.

115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein the reduction or elimination of negative thinking is reflected by an improvement in the scores of at least the BDRS items worthlessness; helplessness and hopelessness; and/or guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 113 to 115, wherein the reduction or elimination of negative thinking is reflected by an improvement in the scores of at least the BDRS items worthlessness; helplessness and hopelessness; and/or guilt at least 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

117. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 113 to 116, wherein the reduction or elimination of negative thinking is reflected by an improvement in the scores of at least the BDRS items worthlessness; helplessness and hopelessness; and/or guilt on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

118. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 113 to 117, wherein the reduction or elimination of negative thinking is reflected by an improvement in the scores of at least the BDRS items worthlessness; helplessness and hopelessness; and/or guilt at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

119. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 113 to 118, wherein the reduction or elimination of negative thinking is reflected by an improvement in the scores of at least the BDRS items worthlessness; helplessness and hopelessness; and/or guilt at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

120. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein a reduction or elimination of negative thinking as reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

121. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 120, wherein the reduction or elimination of negative thinking as reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

122. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 120, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

123. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 120, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

124. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein the reduction or elimination of negative thinking is reflected by an improvement in the score of at least the MADRS item Pessimistic Thinking at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

125. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 124, wherein the reduction or elimination of negative thinking is reflected by an improvement in the score of the MADRS item Pessimistic Thinking at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

126. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114, 124 or 125, wherein the reduction or elimination of negative thinking is reflected by an improvement in the score of at least the MADRS item Pessimistic Thinking on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

127. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 113, 114 or 124 to 126, wherein the reduction or elimination of negative thinking is reflected by an improvement in the score of at least the MADRS item Pessimistic Thinking on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

128. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 113, 114 or 124 to 127, wherein the reduction or elimination of negative thinking is reflected by an improvement in the score of at least the MADRS item Pessimistic Thinking on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

129. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein a reduction or elimination of negative thinking as reflected by an improvement in the MADRS item pessimistic thinking score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

130. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 129, wherein the reduction or elimination of negative thinking as reflected by an improvement in the MADRS item pessimistic thinking score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

131. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 129, wherein the reduction or elimination of negative thinking as reflected by an improvement in the MADRS item pessimistic thinking score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

132. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 129, wherein the reduction or elimination of negative thinking as reflected by an improvement in the MADRS item pessimistic thinking score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

133. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score of the BPRS item Feelings of Guilt at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

134. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 133, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score of the BPRS item Feelings of Guilt at least on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

135. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114, 133 or 134, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score of the BPRS item Feelings of Guilt at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

136. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 133 to 135, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score of the BPRS item Feelings of Guilt at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

137. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 133 to 136, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score of at least the BPRS item Feelings of Guilt on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

138. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein a reduction or elimination of negative thoughts as reflected by an improvement in the score of the BPRS item Feelings of Guilt occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

139. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score of the BPRS item Feelings of Guilt persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

140. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score of the BPRS item Feelings of Guilt persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

141. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score of the BPRS item Feelings of Guilt persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

142. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113 or 114, wherein the patient suffers from negative thinking, and improvement in negative thinking is reflected in a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

143. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 142, wherein the patient suffers from negative thinking, and improvement in negative thinking is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

144. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114, 142 or 143, wherein the patient suffers from negative thinking, and improvement in negative thinking is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

145. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 113, 114 or 142 to 144, wherein the patient suffers from negative thinking, and improvement in negative thinking is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

146. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 113, 114 or 142 to 145, wherein the patient suffers from negative thinking, and improvement in negative thinking is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

147. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 112, wherein the patient suffers from negative thinking, and improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

148. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 147, wherein the improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

149. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 147, wherein the improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

150. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 147, wherein the improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

151. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 150, wherein the patient suffers from anxiety, and the treatment reduces or eliminates the anxiety.

152. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, wherein the reduction or elimination of anxiety is reflected by an improvement in the BDRS item anxiety score at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

153. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 152, wherein the reduction or elimination of anxiety is reflected by an improvement in the score of the BDRS item anxiety at least on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

154. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 151 to 153, wherein the reduction or elimination of anxiety is reflected by an improvement in the BDRS item anxiety score at least on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

155. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 151 to 154, wherein the reduction or elimination of anxiety is reflected by an improvement in the BDRS item anxiety score at least on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

156. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 151 to 155, wherein the reduction or elimination of anxiety is reflected by an improvement in the BDRS item anxiety score at least on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

157. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, wherein the reduction or elimination of anxiety as reflected by an improvement in the BDRS item anxiety score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

158. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the BDRS item anxiety score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

159. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the BDRS item anxiety score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

160. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the BDRS item anxiety score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

161. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, wherein the reduction or elimination of anxiety is reflected by an improvement in the score of the BPRS item anxiety at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

162. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 161, wherein the reduction or elimination of anxiety is reflected by an improvement in the BPRS item anxiety score at least on day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

163. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, 161 or 162, wherein the reduction or elimination of anxiety is reflected by an improvement in the score of the BPRS item anxiety at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

164. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 161 to 163, wherein the reduction or elimination of anxiety is reflected by an improvement in the score of the BPRS item anxiety at least on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

165. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 161 to 164, wherein the reduction or elimination of anxiety is reflected by an improvement in the score of at least the BPRS item anxiety on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

166. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, wherein the reduction or elimination of anxiety as reflected by an improvement in the BPRS item anxiety score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

167. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the BPRS item anxiety score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

168. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the BPRS item anxiety score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

169. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the BPRS item anxiety score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

170. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

171. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 170, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

172. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151, 170 or 171, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

173. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 170 to 172, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

174. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 151 or 170 to 173, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

175. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 150, wherein the patient suffers from anxiety, and wherein improvement in anxiety as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

176. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 175, wherein the improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

177. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 175, wherein the improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

178. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 175, wherein the improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

179. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 178, wherein the patient suffers from cognitive impairment, and the treatment reduces or eliminates the cognitive impairment.

180. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of the BDRS item Impaired Concentration and Memory at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

181. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 180, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the scores of impaired concentration and memory of at least the BDRS items on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

182. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 179 to 181, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the scores of impaired concentration and memory of at least the BDRS items on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

183. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 179 to 182, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of at least the BDRS items Impaired Concentration and Memory on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

184. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 179 to 183, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of at least the BDRS items Impaired Concentration and Memory on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

185. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the scores of the BDRS items Impaired Concentration and Memory occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

186. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 185, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the scores of the BDRS items Impaired Concentration and Memory persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

187. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 185, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the scores of the BDRS items Impaired Concentration and Memory persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

188. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 185, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the scores of the BDRS items Impaired Concentration and Memory persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

189. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of the difficulty in concentration item on the MADRS at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

190. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 189, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of the MADRS item Difficulty in Concentration at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

191. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, 189 or 190, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of at least the MADRS item Difficulty in Concentration on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

192. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 189 to 191, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of at least the difficulty in concentration item of the MADRS on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

193. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 189 to 192, wherein the reduction or elimination of cognitive dysfunction is reflected by an improvement in the score of at least the difficulty in concentration item of the MADRS on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

194. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the score of the MADRS item Difficulty in Concentration occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

195. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 194, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the score of the MADRS item Difficulty in Concentration persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

196. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 194, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the score of the MADRS item Difficulty in Concentration persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

197. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 194, wherein the reduction or elimination of cognitive dysfunction as reflected by an improvement in the score of the MADRS item Difficulty in Concentration persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

198. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, wherein the patient suffers from cognitive impairment, and improvement in cognitive impairment is reflected in a decrease in Clinical Global Impression-Severity Index [CGI-S] score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

199. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 198, wherein the patient suffers from cognitive impairment, and wherein improvement in cognitive impairment is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

200. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179, 198 or 199, wherein the patient suffers from cognitive impairment, and wherein improvement in cognitive impairment is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

201. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 198 to 200, wherein the patient suffers from cognitive impairment, and improvement in cognitive impairment is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

202. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 179 or 198 to 201, wherein the patient suffers from cognitive impairment, and improvement in cognitive impairment is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

203. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 178, wherein the patient suffers from cognitive impairment, and wherein improvement in cognitive impairment as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

204. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 203, wherein the improvement in cognitive dysfunction, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

205. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 203, wherein the improvement in cognitive dysfunction, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

206. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 203, wherein the improvement in cognitive dysfunction, as reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

207. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 206, wherein the patient suffers from social/emotional withdrawal or isolation, and the treatment reduces or eliminates the social/emotional withdrawal or isolation.

208. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, wherein the treatment reduces or eliminates at least one of anhedonia, emotional withdrawal and emotional dullness.

209. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the scores of at least the BDRS items anhedonia, emotional withdrawal, and/or emotional blunting at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

210. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207 to 209, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the scores of at least the BDRS items anhedonia, emotional withdrawal and/or emotional blunting on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

211. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207 to 210, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the scores of at least the BDRS items anhedonia, emotional withdrawal and/or emotional blunting on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

212. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207 to 211, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the scores of at least the BDRS items anhedonia, emotional withdrawal and/or emotional blunting on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

213. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207 to 212, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the scores of at least the BDRS items anhedonia, emotional withdrawal and/or emotional blunting on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

214. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein a reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in scores of the BDRS items anhedonia, emotional withdrawal, and/or emotional blunting occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

215. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 214, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in scores of the BDRS items anhedonia, emotional withdrawal, and/or emotional blunting persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

216. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 214, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in scores on the BDRS items anhedonia, emotional withdrawal, and/or emotional blunting persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

217. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 214, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in scores on the BDRS items anhedonia, emotional withdrawal, and/or emotional blunting persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

218. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the MADRS item Alexithymia at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

219. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 218, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the MADRS item apathy on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

220. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208, 218 or 219, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the MADRS item sensory apathy on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

221. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207, 208 or 218 to 220, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the MADRS item sensory apathy on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

222. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207, 208 or 218 to 221, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the MADRS item sensory apathy on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

223. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein a reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the MADRS item apathy score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

224. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 223, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the MADRS item apathy score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

225. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 223, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the MADRS item apathy score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

226. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 223, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the MADRS item sensory apathy score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

227. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Emotional Withdrawal at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

228. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 227, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Emotional Withdrawal at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

229. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208, 227 or 228, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Emotional Withdrawal at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

230. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 207, 208 or 227 to 229, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Emotional Withdrawal at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

231. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 207, 208 or 227 to 230, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the BPRS item Emotional Withdrawal at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

232. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein a reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Emotional Withdrawal occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

233. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 232, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Emotional Withdrawal persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

234. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 232, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Emotional Withdrawal persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

235. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 232, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Emotional Withdrawal persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

236. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Blunted Affect at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

237. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 236, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Blunted Affect at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

238. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208, 236 or 237, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Blunted Affect at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

239. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 236 to 238, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of the BPRS item Blunted Affect at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

240. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 207, 208 or 236 to 239, wherein the reduction or elimination of social/emotional withdrawal or isolation is reflected by an improvement in the score of at least the BPRS item Blunted Affect at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

241. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein a reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Blunted Affect occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

242. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 241, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Blunted Affect is sustained for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

243. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 241, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Blunted Affect is sustained for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

244. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 241, wherein the reduction or elimination of social/emotional withdrawal or isolation as reflected by an improvement in the score of the BPRS item Blunted Affect is sustained for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

245. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207 or 208, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein improvement in social/emotional withdrawal or isolation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

246. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 245, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein improvement in social/emotional withdrawal or isolation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

247. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208, 245 or 246, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein improvement in social/emotional withdrawal or isolation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

248. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 245 to 247, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein improvement in social/emotional withdrawal or isolation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

249. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 207, 208 or 245 to 248, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein improvement in social/emotional withdrawal or isolation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

250. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 206, wherein the patient suffers from social/emotional withdrawal or isolation, and wherein at least an improvement in the social/emotional withdrawal or isolation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score.

251. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 250, wherein the improvement in social/emotional withdrawal or isolation, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

252. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 251, wherein the improvement in social/emotional withdrawal or isolation, as reflected by a decrease in at least the Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

253. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 251, wherein the improvement in social/emotional withdrawal or isolation, as reflected by a decrease in at least the Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

254. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 253, wherein the treatment reduces or eliminates suicidal ideation.

255. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of the BDRS item Suicidal Ideation at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

256. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 255, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of the BDRS item Suicidal Ideation at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

257. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 254 to 256, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the BDRS item suicidal ideation score at least 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

258. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 254 to 257, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the BDRS item suicidal ideation score at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

259. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 254 to 258, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of at least the BDRS item suicidal ideation on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

260. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, wherein a reduction or elimination of suicidal ideation as reflected by an improvement in the BDRS item suicidal ideation score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

261. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 260, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the BDRS item suicidal ideation score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

262. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 260, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the BDRS item suicidal ideation score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

263. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 260, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the BDRS item suicidal ideation score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

264. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of at least the MADRS item Suicidal Ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

265. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 264, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of the MADRS item Suicidal Ideation at least on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

266. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, 264 or 265, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of at least the MADRS item Suicidal Ideation on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

267. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 264 to 266, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of at least the MADRS item Suicidal Ideation on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

268. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 264 to 267, wherein the reduction or elimination of suicidal ideation is reflected by an improvement in the score of at least the MADRS item Suicidal Ideation on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

269. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, wherein a reduction or elimination of suicidal ideation as reflected by an improvement in the MADRS item suicidal ideation score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

270. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the MADRS item suicidal ideation score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

271. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the MADRS item suicidal ideation score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

272. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the MADRS item suicidal ideation score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

273. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, wherein the patient suffers from suicidal ideation, and improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

274. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 273, wherein the patient suffers from suicidal ideation, and improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

275. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254, 273 or 274, wherein the patient suffers from suicidal ideation, and improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 7 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

276. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 273 to 275, wherein the patient suffers from suicidal ideation, and improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 14 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

277. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 254 or 273 to 276, wherein the patient suffers from suicidal ideation, and improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity Index [CGI-S] score on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

278. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 253, wherein the patient suffers from suicidal ideation, and wherein improvement in suicidal ideation as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

279. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 278, wherein the improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

280. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 278, wherein the improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

281. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 278, wherein the improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity Inventory [CGI-S] score, persists for at least 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

282. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 281, wherein the treatment reduces or eliminates at least one of the following: psychotic symptoms; irritability; instability; increased motor drive; increased speech; and agitation.

283. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 282, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

284. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 282, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

285. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 282, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

286. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 282, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for at least 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

287. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 282, wherein the patient is a lactating woman who has been advised to discontinue breastfeeding for at least 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

288. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in embodiments 1 to 287, wherein the treatment improves maternal function.

289. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 288, wherein the improvement is directed to one or more, and particularly two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, maternal psychosocial well-being, social support, management, and adaptation.

290. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 288 or 289, wherein the BIMF score is improved by at least 10%, preferably at least 20%.

Additional Specific Items

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of mental or nervous system disorders in mothers of children under 18 months of age, wherein 5-MeO-DMT is administered by intravenous, intramuscular or subcutaneous route.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 1, wherein the mental or nervous system disorder involves one or more symptoms selected from sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 1 or 2, wherein the patient suffers from a treatment-resistant form of the disorder.

4. As used in item 3, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, improvement in disability as reflected by a decrease in CGI-S score is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after; on day 7; on day 14; and/or on day 28.

5. As 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 3, improvement in disability as reflected by a decrease in CGI-S score occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

6. As used in item 3 or 5, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the improvement in disability as reflected by a decrease in CGI-S score persists for at least 6 days; particularly for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 6, wherein the patient additionally suffers from mildly impaired, impaired or severely impaired maternal function.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 7, wherein the patient has a Barkin Index of Maternal Function (BIMF) score of 95 or less, such as 80 or less, in particular 65 or less.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 8, wherein the treatment improves maternal function.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 9, wherein the improvement is directed to one or more, and particularly two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, maternal psychosocial well-being, social support, management, and adaptation.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 8 to 10, wherein the BIMF score is improved by at least 10%, preferably at least 20%.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 11, wherein the patient is administered 5-MeO-DMT or a salt thereof in a dose or dosage regimen that provides a peak hallucinogenic experience.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 12, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 12, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 12, wherein a dosage of about 1 mg; or about 2 mg; or about 3 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 13, wherein 5-MeO-DMT or a salt thereof is administered as a first dose for the first administration; and 5-MeO-DMT or a salt thereof is administered as 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration, unless the patient experiences a peak hallucinatory experience.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 13 or 16, wherein 5-MeO-DMT is administered in a dosage of about 1 mg to about 3 mg for a first administration, which is then increased to a dosage of about 4 mg to about 6 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and which is then increased to a dosage of about 7 mg to about 9 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 17, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 13 or 16, wherein 5-MeO-DMT is administered in a dosage of about 0.5 mg to about 1.5 mg for a first administration, which is then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and which is then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 19, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 16 to 20, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 1 to 4 hours, preferably about 1 to 2 hours.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 12 to 21, wherein the occurrence of a peak hallucinatory experience is identified by achievement of at least 60% of the maximum possible score on each of the four subscales (Mystery, Positive Mood, Transcendence of Time and Space, and Ineffable) of the 30-item Revised Mystical Experiences Questionnaire [MEQ30], or by achievement of at least 60% of the maximum possible score on the Oceanic Boundlessness [OBN] dimension of the Altered States of Consciousness [ASC] questionnaire, or by achievement of a Peak Experience Scale [PES] total score of at least 75.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 22, wherein the occurrence of a peak hallucinatory experience is identified by the achievement of a Peak Experience Scale [PES] total score of at least 75.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 23, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

25. As 5-MeO-DMT for use as in items 1 to 24, wherein the disorders are disorders characterized by depressive episodes, for example, major depressive disorder [MDD], persistent depressive disorder, seasonal affective disorder, and bipolar disorders [BD] such as bipolar I disorder and bipolar II disorder; anxiety disorders, for example, separation anxiety disorder, agoraphobia, generalized anxiety disorder [GAD], social anxiety disorder [SAD], panic disorder, phobias, and substance/drug induced anxiety disorder; somatic symptom disorders; obsessive-compulsive and related disorders, for example, obsessive-compulsive disorder [OCD] and body dysmorphic disorder [BDD]; post-traumatic stress disorder [PTSD]; pain disorders, for example, chronic pain, fibromyalgia, and migraine; mental and behavioral disorders due to the use of psychoactive substances, for example, substance use disorders [SUD]; psychotic disorders, for example, schizophrenia; eating disorders; attention-deficit/hyperactivity disorder [ADHD]; Personality disorders, such as schizotypal and borderline personality disorders; autism spectrum disorders; chronic fatigue syndrome; and mental or neurological disorders associated with HIV, post-COVID conditions, or traumatic brain injury.

26. As 5-MeO-DMT for use as in items 1 to 25, the patient suffers from sleep disturbance.

27. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for at least 6 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for at least 3 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein the patient is a lactating mother who has been advised to discontinue breastfeeding for at least 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Additional Specific Items

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of mental or nervous system disorders in lactating women,

A dosage of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt is administered as a single dose or as the highest dose in a dose escalation schedule with an interval between doses of at least about 1 hour,

5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous route,

The patient is advised to temporarily discontinue breastfeeding.

2. For use as in item 1, it is recommended that breastfeeding be temporarily discontinued at least 1 hour before the first dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof and that breastfeeding be resumed at least 24 hours after the last dose.

3. For use as in item 1, it is recommended that breastfeeding be temporarily discontinued at least 1 hour before the first dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof and that breastfeeding be resumed at least 12 hours after the last dose.

4. For use as in item 1, it is recommended that breastfeeding be temporarily discontinued at least 1 hour before the first dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof and that breastfeeding be resumed at least 6 hours after the last dose.

5. For use as in item 1, it is recommended that breastfeeding be temporarily discontinued at least 1 hour before the first dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof and that breastfeeding be resumed at least 2 hours after the last dose.

6. For use as in item 1, it is recommended that the mother temporarily discontinue breastfeeding at least 1 hour before receiving the first dose of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof and not resume breastfeeding until at least 1 hour after the last dose.

7. For use as in item 1, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and to resume breastfeeding at least 24 hours after the last dose.

8. For use as in item 1, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and to resume breastfeeding at least 12 hours after the last dose.

9. For use as in item 1, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and to resume breastfeeding at least 6 hours after the last dose.

10. For use as in item 1, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and to resume breastfeeding at least 2 hours after the last dose.

11. For use as in item 1, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and to resume breastfeeding at least 1 hour after the last dose.

12. As for 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 1, patients are advised to temporarily discontinue breastfeeding only for the duration of the actual treatment.

13. For use as in items 1 to 12, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until they are ready for discharge.

14. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 13, the decision to be ready for discharge occurs approximately 1 hour after the last dose.

15. For use as in items 13 or 14, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised not to resume breastfeeding before discharge or 6 hours after the last dose, whichever is later.

16. For use as in items 1 to 15, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised not to resume breastfeeding before the later of discharge or 3 hours after the last dose.

17. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 15, patients are advised not to resume breastfeeding before the later of discharge or 2 hours after the last dose.

18. For use as in items 1 to 15, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised not to resume breastfeeding before the later of discharge or 1 hour after the last dose.

19. For use as in items 1 to 18, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until at least 24 hours after the last dose and to discard all breast milk expressed during the 24-hour period.

20. For use as in items 1 to 18, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, patients are advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until at least 2.5 hours after the last dose and to express and discard breast milk 2.5 hours after the last dose.

21. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 20, patients are advised to express and discard breast milk 24 hours after the last dose before resuming breastfeeding.

22. As 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 21, patients are advised to breastfeed their child no more than twice during the first 12 hours after the last dose.

23. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 22, wherein any expressed breast milk is discarded as long as the concentration of 5-MeO-DMT and/or 5-MIAA in the breast milk exceeds a predetermined threshold.

24. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 23, wherein the threshold for 5-MeO-DMT is 2000 pg.

25. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 23, wherein the threshold for 5-MeO-DMT is 500 pg.

26. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 23, wherein the threshold for 5-MeO-DMT is 75 pg.

27. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 23 to 26, wherein the threshold for 5-MIAA is 14000 pg.

28. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 23 to 26, wherein the threshold for 5-MIAA is 2000 pg.

29. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 23 to 26, wherein the threshold for 5-MIAA is 75 pg.

30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 22, wherein breastfeeding is resumed when the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk is below a predetermined threshold.

31. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 30, wherein the threshold for 5-MeO-DMT is 2000 pg.

32. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 30, wherein the threshold for 5-MeO-DMT is 500 pg.

33. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in item 30, wherein the threshold for 5-MeO-DMT is 75 pg.

34. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 30 to 33, wherein the threshold for 5-MIAA is 14000 pg.

35. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 30 to 33, wherein the threshold for 5-MIAA is 2000 pg.

36. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 30 to 33, wherein the threshold for 5-MIAA is 75 pg.

37. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 36, wherein breastfeeding is configured such that the DID of 5-MeO-DMT per kg of infant body weight is not more than 1 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the configuration is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

38. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 36, wherein breastfeeding is structured so that the DID of 5-MeO-DMT per kg of infant body weight is not more than 0.4 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the structure is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

39. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 36, wherein breastfeeding is configured such that the DID of 5-MeO-DMT per kg of infant body weight is not more than 0.2 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the configuration is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

40. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 39, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 10% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 39, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 5% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

42. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 39, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 1% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 42, wherein breastfeeding is configured such that the DID of the final metabolite 5-MIAA per kg of infant body weight is less than or equal to 4 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the configuration is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 42, wherein breastfeeding is configured such that the DID of the final metabolite 5-MIAA per kg of infant body weight is less than or equal to 2 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the configuration is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

45. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 42, wherein breastfeeding is configured such that the DID of the final metabolite 5-MIAA per kg of infant body weight is less than or equal to 1 μg/kg/day during the first 24 hours after resumption of breastfeeding, and the configuration is selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

46. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 45, wherein the breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 4% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

47. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 45, wherein the breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 2% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

48. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 45, wherein the breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 1% or less during the first 24 hours after resumption of breastfeeding, the configuration being selected by appropriate timing for resumption of breastfeeding, appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 48, wherein the patient suffers from PPD.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in claim 49, wherein relief of depressive symptoms, as assessed by a MADRS score of 10 or less, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 50, wherein relief of depressive symptoms, as assessed by a HAM-D score of 7 or less, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 51, wherein maternal function is improved as reflected by improvement in the functional domain of the Barkin Index of Maternal Functioning (BIMF) of maternal mother-infant interaction and psychological well-being.

53. As used in item 52, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the cumulative score improvement of the BIMF scale item reflecting psychological well-being is at least 25%, and the cumulative score improvement of the BIMF scale item responding to mother-child interaction is at least 5%.

54. As used in item 52 or 53, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein improvement in the MADRS items of listlessness, pessimism, apathy, internal tension and/or decreased sleep leads to an increase in the BIMF scale score reflecting psychosocial well-being, and improvement in the MADRS items of apathy and internal tension leads to an increase in the BIMF scale score reflecting mother-child interaction.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 54, wherein the patient suffers from a mental or neurological disorder comprising one or more symptoms selected from sleep disturbance and anxiety, each of which impairs maternal function.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 55, wherein the patient suffers from a mental or nervous disorder including anxiety symptoms, wherein the treatment reduces or eliminates anxiety symptoms, particularly of internal tension.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 56, wherein treatment leads to a clinical response as reflected by a decrease in HAM-A score of at least 50% compared to the respective score prior to treatment, about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 56 or 57, wherein the treatment leads to a clinical response as reflected by a decrease in HAM-A score of at least 50% compared to the respective score prior to treatment on day 1, e.g., about 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 56 to 58, wherein treatment leads to a clinical response as reflected by a decrease in HAM-A score of at least 50% compared to the respective score prior to treatment, at about 7 days following the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 56 to 59, wherein treatment leads to a clinical response as reflected by a decrease in HAM-A score of at least 50% compared to the respective score prior to treatment, at about 14 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 56 to 60, wherein treatment leads to a clinical response as reflected by a decrease in HAM-A score of at least 50% compared to the respective score prior to treatment, at about 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 55 to 61, wherein the patient suffers from a mental or neurological disorder including symptoms of sleep disturbance, and the treatment reduces or eliminates the symptoms of sleep disturbance.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 62, wherein the patient suffers from sleep disturbance as reflected by a Pittsburgh Sleep Quality Index (PSQI) overall score greater than 5.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 62 to 63, wherein the treatment reduces or eliminates sleep disturbance, and the reduction or elimination of sleep disturbance is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period is from the time when the acute hallucinatory experience has subsided after the last administration until the time of assessment.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 62 to 64, wherein treatment success is indicated by a decrease in the PSQI overall score.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 62 to 65, wherein treatment success is indicated by a decrease in at least four of the seven components of the PSQI.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 62 to 66, wherein treatment success is indicated by a decrease in the PSQI overall score to 5 points or less.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 62 to 67, wherein the sleep disorder is insomnia.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 68, wherein the patient is administered 5-MeO-DMT or a salt thereof in a dose or dosage regimen that provides a peak hallucinogenic experience.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69, wherein a dosage of about 1 mg; or about 2 mg; or about 3 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69, wherein a dosage of about 2 mg; or about 4 mg; or about 6 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69, wherein 5-MeO-DMT or a salt thereof is administered as a first dose for the first administration; and 5-MeO-DMT or a salt thereof is administered as 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration, unless the patient experiences a peak hallucinatory experience.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69 or 73, wherein 5-MeO-DMT is administered in a dosage of about 1 mg to about 3 mg for a first administration, which is then increased to a dosage of about 4 mg to about 6 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and which is then increased to a dosage of about 7 mg to about 9 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 74, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69 or 73, wherein 5-MeO-DMT is administered in a dosage of about 0.5 mg to about 1.5 mg for a first administration, which is then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and which is then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 76, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 69 or 73, wherein 5-MeO-DMT is administered in a dosage of about 2 mg to about 3 mg for a first administration, which is then increased to a dosage of about 4 mg to about 5 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and which is then increased to a dosage of about 6 mg to about 7.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 78, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 4 mg, and the third dose of 5-MeO-DMT is about 6 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 73 to 79, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

81. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as in items 1 to 69,

A dosage of about 1 mg to about 5 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt is administered as a single dose or as the highest dose in a dose escalation schedule with an interval between doses of at least about 1 hour,

5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous route,

The patient is advised to temporarily discontinue breastfeeding.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 81, in a dosage of about 1 mg; or about 5 mg, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 82, wherein 5-MeO-DMT or a salt thereof is administered in a first dose and for the first administration; 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations; each subsequent administration uses a higher dose than the previous administration unless the patient experiences the highest psychedelic experience.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 83, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 69 to 84, wherein the occurrence of a peak hallucinatory experience is identified by achievement of at least 60% of the maximum possible score on each of the four subscales (Mystery, Positive Mood, Transcendence of Time and Space, and Indescribable) of the 30-item Revised Mystical Experiences Questionnaire [MEQ30], or by achievement of at least 60% of the maximum possible score on the Oceanic Boundless [OBN] dimension of the Altered States of Consciousness [ASC] questionnaire, or by achievement of a Peak Experience Scale [PES] total score of at least 75.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 85, wherein the occurrence of a peak hallucinatory experience is identified by the achievement of a Peak Experience Scale [PES] total score of at least 75.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 86, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

Example

The following examples are provided to aid in understanding the present invention and are not intended to limit the invention described in the claims below in any way, and should not be construed as such.

Example 1 - Production and administration of 5-MeO-DMT aerosol

Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask such that a 200 μl solution volume contains the target dose of 5-MeO-DMT free base to be administered by inhalation to a volunteer or patient. A typical target dose is 1 mg to 25 mg of 5-MeO-DMT. For example, for a target dose of 18 mg of 5-MeO-DMT, 90 mg of 5-MeO-DMT would be dissolved in 100% ethanol to a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

Step 2: Transfer 200 μl of the solution to a dosing capsule containing a drip pad (Storz & Bickel, Germany) and close the dosing capsule with its cap.

Step 3: Transfer the dosing capsules filled with the 5-MeO-DMT ethanol solution into the filling chamber of the first Volcano Medic vaporizer, which is preheated to a temperature set at 55°C. The vaporizer's airflow is then switched on at a preset rate of approximately 12 l/min for 60 seconds. The heated air flows through the dosing capsules, causing the ethanol to evaporate, leaving the target dose of 5-MeO-DMT in a thin layer covering the stainless steel wire mesh. The correct preparation of the dosing capsules can be verified by comparing the final weight gain of the capsules to the weight of an empty capsule and verifying that the target dose of 5-MeO-DMT is approximately equal to the target weight.

Step 4: Remove the prepared dosing capsules from the filling chamber. Then, transfer them to the filling chamber of a second Volcano Medic vaporizer preheated to a temperature set at 210°C. Turn on the airflow for at least 5 minutes, then turn it off just before transfer. Attach the inhalation balloon (Storz & Bickel, Germany) with valve to the socket of the filling chamber, close the filling chamber tightly, and immediately turn on the airflow switch at a preset flow rate of approximately 12 1/min for exactly 15 seconds, then turn it off. This will aerosolize the entire dose of 5-MeO-DMT and distribute it into approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT can be confirmed by verifying that the capsule weight returns to approximately its initial weight.

Step 5: The balloon is then removed from the filling chamber, which automatically closes the valve. After attaching the mouthpiece to the balloon, the aerosol is ready for immediate administration to the volunteer or patient.

Step 6: To prepare for administration, the patient is asked to take one or two deep inhalations, initially with a full exhalation, and then complete this sequence with a full exhalation. Then, while holding the mouthpiece firmly against the lips, the patient inhales the entire volume of the inhalation balloon in one puff, holds their breath for 10 seconds (±2.5 seconds), and then exhales normally. Upon completion of the inhalation procedure, the patient will be instructed to lie down.

Details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020/169850 A1, the contents of which are incorporated herein by reference.

Example 2 - Preparation of high-purity 5-MeO-DMT

5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 vol) at 35°C to 40°C and cooled to room temperature over 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed, so the batch temperature was lowered to 7°C to 12°C over 30 minutes. After stirring at 7°C to 12°C for 10 minutes, crystallization occurred. The batch was subsequently stirred at 7°C to 12°C for 1 hour and then filtered. After washing with MTBE (1 mL, 0.5 vol), the batch was dried under vacuum at 7°C to 12°C for 3.5 hours, yielding 1.02 g (50% recovery) of a pale orange solid. The isolated solid was analyzed for purity by HPLC as described in WO 2020/169850 A1. The purity was confirmed to be 99.74% by area.

The analytical results further indicate that individual impurity levels are less than 0.10 area %. Solvent analysis of the sample indicated a MTBE level of 17 ppm.

Example 3 - Preparation of 5-MeO-DMT hydrobromide salt

5-MeO-DMT HBr was prepared in a 100 mg scale.

5-MeO-DMT free base was combined with isopropyl acetate (10 vol), and the resulting 5-MeO-DMT solution was heated to 50°C. HBr (1 M in ethanol, 1 eq) was added in a single aliquot. The mixture was maintained at temperature and equilibrated for 3 h.

After 1 hour, a suspension was formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was separated by filtration and dried under vacuum at 40°C for 18 hours.

A white crystalline material was obtained.

The salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern comprising peaks at 14.5°2θ±0.2°2θ; 16.7°2θ±0.2°2θ; 17.0°2θ±0.2°2θ; 20.6°2θ±0.2°2θ; 20.7°2θ±0.2°2θ; 21.4°2θ±0.2°2θ; 24.2°2θ±0.2°2θ; 24.8°2θ±0.2°2θ; 25.3°2θ±0.2°2θ; 27.4°2θ±0.2°2θ, measured using Cu Kα radiation.

Example 4 - Measurement of inhibitory constants for central 5-HT1A and 5-HT2A receptors in postmortem human brain membrane preparations.

In this study, the affinities of three hallucinogenic test compounds (psilocin, DMT and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue from the hippocampus and prefrontal cortex, respectively, were measured using a radioligand binding technique.

Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors were under 65 years of age and had died suddenly within 72 hours of death, with no history of coma, mental or neurological disorders.

Binding to 5-HT1A receptors in postmortem human hippocampus

Hippocampi were homogenized in ice-cold 0.25 M sucrose (1:30 w/v) using a motorized Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice, and the pellet was re-homogenized in 0.25 M sucrose (1:15 w/v) and centrifuged at 750 g for 10 min. The combined supernatants were diluted in ice-cold membrane preparation buffer (1:100 w/v) and centrifuged at 20,500 g for 10 min using a fitted glass/Teflon homogenizer (12 strokes, 800 rpm). The pellet was resuspended in ice-cold membrane preparation buffer, incubated at 37°C for 10 minutes, and centrifuged at 20,500 xg for 10 minutes. The tissue was washed by resuspending the pellet and centrifuging one last time (20,500 xg for 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration of 3.125 mg of tissue wet weight/ml. All centrifugations were performed at 4°C. Membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl ₂ , and 0.1% ascorbic acid. Assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl ₂ , 0.1% ascorbic acid, and 10 μM pargylin.

For saturation binding assays, hippocampal membranes (400 μl; equivalent to 1.25 mg wet tissue weight/tube) were incubated with 50 μl of 0.075–9.6 nM [ ³ H]8-OH-DPAT and 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) at 25 °C for 30 min. Wash buffer consisted of 50 mM Tris, pH 7.7.

In the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet tissue weight/tube) were incubated at 25 °C for 30 min with 50 μl of 0.6 nM [ ³ H]8-OH-DPAT and either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) or 50 μl of one of ten test compounds at one of ten concentrations ranging from 1 to 10000 nM.

Membrane-bound radioactivity was recovered by vacuum filtration through a Skatron 11731 filter presoaked in 0.5% polyethylenimine (PEI) using a Skatron cell harvester. The filter was rapidly washed with ice-cold wash buffer (wash setting 0.9.9) and the radioactivity was measured by liquid scintillation counting (1 ml Packard MV Gold scintillator).

Nonlinear regression was used to calculate the concentration of the compound required to inhibit 50% of specific binding (IC ₅₀ ) and the Hill slope. A single-site binding model allowing for ligand depletion was used to calculate K _i .

Binding to 5-HT2A receptors in postmortem human prefrontal cortex

The prefrontal cortex was homogenized in ice-cold 0.25 M sucrose (1:30 w/v) using a motorized Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice, and the pellet was re-homogenized in 0.25 M sucrose (1:15 w/v) and centrifuged at 750 g for 10 min. The combined supernatants were diluted in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 w/v), homogenized using a fitted glass/Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. To wash the tissue, the pellet was centrifuged twice more (20,500 × g for 10 min). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, at a tissue concentration of 10 mg of tissue wet weight/ml. All centrifugations were performed at 4°C.

For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg wet tissue weight/tube) were incubated with 50 μl of 0.00625–0.8 nM [ ³ H]MDL-100,907 and 50 μl of assay buffer or 50 μl of 10 μM ketanserin (nonspecific binding) at 25 °C for 60 min. Assay and wash buffer consisted of 50 mM Tris-HCl buffer, pH 7.4.

In the displacement assay, frontal cortex membranes (400 μl; equivalent to 4 mg wet tissue weight/tube) were incubated with 50 μl of 0.1 nM [3H]MDL-100,907 and 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (nonspecific binding) or 50 μl of one of ten test compounds at one of ten concentrations ranging from 1 to 10000 nM for 60 min at 25°C.

The bound radioactivity was recovered and measured as described above. Data analysis was also conducted as described above.

result

The dissociation constants (K _d values) of [ ³ H]8-OH-DPAT for 5-HT1A receptors in hippocampal membranes of postmortem human brain tissue were measured for each of the three donors. The obtained dissociation constants (K _d values) were 0.51, 0.28, and 0.52 nM, respectively.

The average inhibition constants (K _i values) of psilocin, DMT, and 5-MeO-DMT were 48, 38, and 1.80 nM, respectively (average n = 3). All compounds gave Hill slopes approaching unity, suggesting a single-site binding model.

The dissociation constants (K _d values) of [ ³ H] MDL-100,907 for 5-HT2A receptors in prefrontal cortex membranes of postmortem human brain tissue were determined for three donors. The obtained dissociation constants (K _d values) were 0.11, 0.08, and 0.08 nM, respectively.

The average inhibition constants (K _i values) of psilocin, DMT, and 5-MeO-DMT were 37, 117, and 122 nM, respectively (average n = 3). All compounds gave Hill slopes approaching unity, suggesting a single-site binding model.

The selectivity ratios of psilocin, DMT, and 5-MeO-DMT for 5-HT2A receptors compared to 5-HT1A receptors were 0.78, 3.1, and 68, respectively.

Example 5 - Clinical trial in patients with TRD

A Phase 1/2 clinical trial of 5-MeO-DMT administered via inhalation as described herein was completed in patients with treatment-resistant major depressive disorder (TRD). This trial was designed in two parts. Part A was an open-label, single-arm, single-dose Phase 1 trial using two dose levels [12 mg (n = 4) and 18 mg (n = 4)]. Part B was an open-label, single-arm, Phase 2 trial using an individualized dosing regimen with intrapatient dose escalation using 5-MeO-DMT. Patients (n = 8) received at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) daily, with higher doses administered only if the patient did not achieve peak experience with the previously administered dose. The primary endpoint of Part A was to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in patients with TRD. The primary endpoint of Part B was the effect on depression severity as assessed by the proportion of patients in remission at day 7 post-treatment, defined as a MADRS total score of 10 or less.

In Part A, three of four patients in both groups (12 mg and 18 mg) experienced at least one adverse drug reaction (ADR), all of which were mild and resolved spontaneously. No SAEs were reported.

Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission on Day 7, and one additional patient (25%) in the 18 mg group had a MADRS clinical response on Day 7. The mean MADRS change from baseline on Day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

In Part B, 7 of 8 patients (87.5%) experienced at least one adverse drug reaction (ADR). All ADRs resolved spontaneously. No SAEs were reported.

The primary endpoint was met in 7 of 8 patients (87.5%) who achieved MADRS remission at day 7 (p<0.0001). The mean change from baseline in MADRS at day 7 was 24.4 (76%).

No clinically significant changes were observed in Part A or Part B in any of the safety laboratory analyses, vital signs, mental safety assessments, or measures of cognitive function.

The results are summarized in the table below.

[Table 2-A]

[Table 2-B]

[Table 2-C]

[Table 3-A]

[Table 3-B]

[Table 3-C]

Example 6 - Pharmacokinetic evaluation of 5-MeO-DMT and bufotenine

To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups of eight subjects each were formed. Subjects received a single dose of 6 mg, 12 mg, or 18 mg of 5-MeO-DMT via inhalation. Blood samples were obtained at 1 minute; 2 minutes; 4 minutes; 7 minutes; 10 minutes; 15 minutes; 20 minutes; 30 minutes; 45 minutes; and 1 hour; 1.5 hours; 2 hours; 3 hours; and 4 hours after administration.

5-MeO-DMT concentrations were measured using LC-MS/MS. PK parameters were generated by logarithmic analysis of the concentration versus time plot for each individual. Analyses were performed using Phoenix WinNonlin 6.3 software.

The median Cmax values obtained for the three groups were 11.85 ng/ml (6 mg group), 22.90 ng/ml (12 mg group), and 38.45 ng/ml (18 mg group).

Table 4 below presents the median plasma concentration percentages for Cmax as measured for the indicated time points.

Pharmacokinetic measurements were also performed for dosing regimens that depended on increasing doses. Substantially similar results were obtained.

Blood concentrations of bufotenine, a metabolite of 5-MeO-DMT, were also measured. Only in a few samples did concentrations exceed the lower level of quantification (LLOQ) (25 pg/ml). After 15 minutes, bufotenine concentrations were always below the LLOQ.

A fairly similar observation was made when subjects who received a dose escalation plan were included.

Example 7 - Toxicological testing of 5-MeO-DMT

5-MeO-DMT was nonmutagenic in four histidine-requiring bacterial strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101). These conditions included treatment at a concentration of 5000 μg/plate (the maximum recommended concentration according to current regulatory guidelines) in the absence and presence of the rat liver metabolic activation system (S-9).

Example 8 - 5-MeO-DMT binding to human plasma proteins

In vitro binding of 5-MeO-DMT to plasma proteins was measured using high-throughput dialysis. Equilibrium time and non-specific binding were measured using human plasma at a nominal 5-MeO-DMT concentration of 1 μM. After evaluation of the equilibrium data, plasma protein binding was investigated at nominal concentrations of 0.1, 1, and 10 μM using a 4-h dialysis time. Concentrations of 5-MeO-DMT in samples from the plasma and buffer compartments were determined by LC-MS/MS. Protein binding results are presented below.

Example 9 - Human metabolism of 5-MeO-DMT

5-MeO-DMT was incubated with human hepatocytes suspended in Leibovitz L-15 medium (1 × 106 cells/mL) at nominal concentrations of 1 μM and 10 μM.

A standard stock solution of 5-MeO-DMT was prepared at 20 mM in ethanol and further diluted to a concentration of 2 mM using Leibovitz L-15 medium. For incubation with cryopreserved hepatocytes, the 2 mM stock solution was diluted to a concentration of 20 μM or 2 μM using Leibovitz L-15 medium. Aliquots (250 μL) of the 20 μM and 2 μM test article formulations were added to each hepatocyte incubation sample (250 μL), as appropriate, to give a final test article concentration in the incubation medium of 10 μM or 1 μM, respectively, and to ensure that the incubation medium contained less than 1% (v/v) of solvent.

The incubation was performed in a shaking water bath at approximately 37°C (total incubation volume 0.5 mL). For 1 μM, incubation was terminated by adding ice-cold acetonitrile (0.5 mL) after 0, 5, 10, 20, 30, 60, and 120 min. For 10 μM, incubation was terminated by adding ice-cold acetonitrile containing an internal standard (1 μg/mL psilocin-d10) after 0, 10, 30, 60, and 120 min.

The samples were vortex-mixed and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

Blank control assays were performed using Leibovitz L-15 medium instead of the test substance. Cell-free control samples were performed using Leibovitz L-15 medium instead of hepatocytes. Aliquots of blank control samples were collected at 120 minutes, whereas cell-free control samples were collected at 0, 30, and 120 minutes for the 1 μM assay, and at 0 and 120 minutes for the 10 μM assay.

All 1 μM concentrations were performed in duplicate, whereas all 10 μM concentrations were performed as singlets. All samples were stored at -80 °C (nominal) prior to analysis.

Suitable chromatographic conditions were developed to maintain the parent compound and provide a suitable chromatographic response. Samples generated after incubation with 10 μM 5-MeO-DMT at 0, 30, and 120 minutes were analyzed using reversed-phase LC-MS to generate high- and low-energy mass spectra (MSE). Prior to sample analysis, a 100 μL aliquot of each sample was evaporated to near dryness under a steady stream of nitrogen at room temperature and subsequently reconstituted in 50 μL of mobile phase A (0.1% formic acid in water). Each sample (0, 30, and 120 minutes, 10 μM) was analyzed using accurate mass LC-MS to determine the relative levels of the parent compound at each time point and to profile the metabolites formed. Appropriate blank and control samples were also analyzed. Samples from the 10- and 60-minute, 10 μM incubations were not analyzed and stored at -80 °C (nominal).

Data were examined for the presence of metabolites by comparison of retention times with reference standards of the test substance and based on the exact mass of potential metabolites using screening software (UNIFI version 1.9.4) and user-defined search parameters. To confirm a suspected metabolite, the measured exact mass of the peak detected in the sample used for structural elucidation had to be within 5 ppm of the theoretical mass to confirm the molecular formula.

The results obtained are summarized in Table 1 above.

Example 10 - Metabolic stability of 5-methoxy indole-3-acetic acid (5-MIAA) and 5-methoxytryptopol in a human hepatocyte co-culture model.

The metabolic stability of 5-MIAA and 5-methoxytryptopol was investigated in Hμrel co-culture assays using human hepatocytes (Hμrel HumanPool ^™ , a primary liver co-culture model from Visikol Inc.).

Politics was performed using initial concentrations of 1 and 10 μM and sampling at time points of 0, 1, 2, 4, 8, 24, 48, and 72 h. Samples were analyzed using UPLC/QE-orbitrap-MS.

The remaining LC/MS peak areas detected for the test compounds after each incubation time point using the Hμrel co-incubation assay are shown in the table below compared to the corresponding 0-minute incubation sample. Results (decay half-life) for the black control diazepam indicated that the enzyme activity was within normal levels.

For 5-MIAA, a low metabolic turnover was observed, with remaining abundance after a 72-h period of 75-82% in the presence of hepatocytes, whereas no loss was observed in the hepatocyte control group.

For 5-methoxytryptopol, a high metabolic turnover was observed, with complete elimination within 24 h in the presence of hepatocytes and no elimination in the hepatocyte control group.

Using human hepatocytes and a 1 μM test concentration, an ex vivo intrinsic clearance rate of 0.15 μl/min/million cells (half-life 15 400 min) was observed for 5-MIAA, whereas the corresponding value for 5-methoxytryptopol was 16.2 μl/min/million cells (half-life 142 min).

The predicted liver extraction ratios were 2% for 5-MIAA and 67% for 5-methoxytryptopol.

Example 11 - Plasma binding of 5-MIAA

Binding to human plasma proteins was determined. The unbound fraction (fu) for three replicates, as well as the average unbound fraction, standard deviation, and average % recovery, were reported (Table 8).

Example 12 - Clinical trial of 5-MeO-DMT administered via inhalation to patients with postpartum depression

The single-arm, open-label clinical trial will include 15 adult female patients with clinically diagnosed postpartum depression (PPD).

Patients will receive an individualized daily regimen of 5-MeO-DMT via vaporization followed by inhalation.

More specifically, patients will receive up to three doses of 5-MeO-DMT of 6 mg, 12 mg, and 18 mg on day 0.

1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT.

2. The second dose (12 mg) will be administered only in the following cases:

a. If the peak experience (total score ≥75) is not reached after administration of 6 mg,

b. If the 6 mg dose is deemed safe and well tolerated by the investigator,

c. If any psychoactive effect (PsE) of the previous dose has subsided,

d. If pre-administration vital parameters and forced expiratory volume in one second (FEV1) are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

3. Similarly, the third dose (18 mg) will be administered only in the following cases:

a. If the peak experience (total score ≥75) is not reached after administration of 12 mg,

b. If the 12 mg dose is safe and well tolerated according to the investigator's judgment,

c. If any PsE from the previous volume has settled,

d. If pre-administration vital parameters and forced expiratory volume in 1 second [FEV1] are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

Patients will be evaluated for peak hallucination experience (based on the Patient Rating Visual Analog Scale, PE scale), sedation, and other endpoints after administration. Follow-up visits are scheduled on days 1 and 7 after administration.

All patients considered for participation in a clinical trial must meet the following criteria:

1. Female and between the ages of 18 and 45 (inclusive) at the time of screening.

2. Body mass index (BMI) at screening is in the range of 18.5 and 35 kg/m ² (inclusive).

3. Meets the testing criteria for PPD as assessed by a clinical trial psychiatrist or registered psychologist.

a. Diagnosis of major depressive disorder without psychotic features, with perinatal onset, beginning after pregnancy and within the first 4 weeks postpartum, as confirmed by the Mini-International Neuropsychiatric Interview (MINI).

b. A total score of 28 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS) at screening and before administration on Day 0.

6. You must have stopped breastfeeding at the time of screening, or if you are breastfeeding or breastfeeding at the time of screening, you must temporarily stop breastfeeding from immediately before the study drug dose on Day 0 until 24 hours after the last dose, and if necessary, express and discard all breast milk during that 24-hour period, but agree that you will need to include expressing/discarding milk 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding.

4. Patients must agree to complete abstinence (abstaining from heterosexual intercourse) or use a medically accepted method of contraception with a highly effective (failure rate of <1%) method for 30 days before and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test result at screening and on the day before (Day -1).

5. Willing to delay starting any other antidepressant or anxiety medication until after the trial ends on Day 7 and agree not to change any psychotherapy during the trial.

Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this trial:

1. Based on medical history, psychiatric evaluation, and MINI assessment, a current or past diagnosis of bipolar disorder, manic or hypomanic episode, psychotic disorder, major depressive disorder [MDD] or other mood disorder with psychotic features, obsessive-compulsive disorder, posttraumatic stress disorder [PTSD], autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient ineligible for the study.

2. If you have one or more first- or second-degree relatives who currently or in the past have bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

3. At significant risk for suicide, as determined by a clinical psychiatrist or registered psychologist, based on medical history, psychiatric evaluation, and an assessment of suicidal ideation and suicidal behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS).

4. Antidepressants were taken within 14 days or 5 times the half-life (whichever is longer) prior to the dose (exception: within the last 5 weeks for fluoxetine).

5. Any other drug with monoamine oxidase inhibitor (MAOI) activity was taken within 14 days or 5 half-lives (whichever is longer) prior to administration.

6. Previous serious adverse reactions to hallucinogens or psychedelic drugs (e.g., psilocybin, psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), as determined by the investigator.

7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

8. Any current or past clinically significant condition that, in the judgment of the investigator, would make the patient ineligible for the study [e.g., severe infection, pulmonary disease, uncontrolled hypertension, new-onset gestational hypertensive disorder during pregnancy or the postpartum period (e.g., gestational hypertension, pre-eclampsia-eclampsia, superimposed pre-eclampsia), uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)].

9. Administer any medication or other substance that, in the judgment of the investigator, makes the patient unsuitable for the study.

10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that, in the judgment of the investigator, make the patient unsuitable for the clinical trial.

11. Patients who have a positive pregnancy test at screening or on the day before screening (-1 day), are pregnant, or plan to become pregnant during the clinical trial and up to 90 days after 5-MeO-DMT administration.

12. Patients with a DSM-5 drug or alcohol use disorder within the 6 months prior to screening.

The primary objective of this trial was to determine the onset and 7-day durability of the antidepressant effect of individualized dosing regimens of 6 mg, 12 mg, and 18 mg daily of 5-MeO-DMT in adult female patients with PPD.

Secondary objectives were to determine the antidepressant, anxiolytic, maternal behavior, safety and tolerability, intensity and duration of psychoactive effects [PsE], and cognitive outcomes of individualized dosing regimens of 6 mg, 12 mg, and 18 mg daily of 5-MeO-DMT in adult female patients with PPD.

The exploratory objective was to determine the amounts of 5-MeO-DMT and its metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA), in breast milk, blood, and urine by LC/MS/MS in adult female patients with PPD following administration of daily IDRs of 6 mg, 12 mg, and 18 mg of 5-MeO-DMT (metabolite identification screening tests can be performed as needed).

The primary endpoint of the trial was the assessment of the antidepressant effect of 5-MeO-DMT as measured by change from baseline in the MADRS assessed at day 7.

Secondary endpoints included the antidepressant effect of 5-MeO-DMT, assessed as follows:

The antidepressant effects of 5-MeO-DMT are evaluated by:

○ Proportion of patients achieving remission (MADRS≤10) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in MADRS assessed 2 hours after final test drug administration on Day 0 and on Day 1;

○ Proportion of responders (≥50% decrease from baseline in MADRS total score) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Clinical Global Impression Severity Scale [CGI-S] 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

Effects on maternal behavior as assessed by changes from baseline in the Barkin Maternal Functioning Index [Barkin Index of Maternal Functioning, BIMF] total and subscale scores by day 7;

Exposure to 5-MeO-DMT and bufotenine in breast milk obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, in the evening of day 0, and on days 1 and 7;

Exposure of 5-MeO-DMT and bufotenine in blood obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, and on days 1 and 7;

The safety and tolerability of 5-MeO-DMT were evaluated as follows.

○ Reporting of treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak flow apnea measurements;

○ Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA/S]) after each dose (when PsE subsides and 60 minutes after each study drug administration) and as part of the discharge assessment on Day 0;

○ Change from baseline on the Clinician-Administered Dissociative State Scale (CADSS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline on the Brief Mental State Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline in the C-SSRS assessed as part of the discharge assessment on days 0, 1, and 7;

○ Change from baseline in YMRS assessed as part of the discharge assessment on days 0, 1, and 7;

Patients experienced PsE as reported 30 to 60 minutes after each dose when the PsE subsided:

○ PsE assessment using the Peak Experience [PE] scale to evaluate PE achievement (PE scale total score ≥ 75);

○ Challenge Experience Questionnaire [CEQ];

○ Mystical Experience Questionnaire [MEQ-30];

Duration of PsE, defined as the time from test drug administration until PsE subsides (scores by investigator and patient), is completed 30 to 60 minutes after each dose.

To date, one patient with postpartum depression diagnosed by a psychiatrist participated in the clinical trial. The diagnosis was perinatal-onset major depressive disorder without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2), with onset occurring during pregnancy and within the first 4 weeks postpartum. The patient was diagnosed with postpartum depression after the birth of her third child. The patient completed all scheduled visits. The inhalation procedure was performed appropriately and was well tolerated, with no inhalation-related adverse events.

result

Aside from a transient, clinically irrelevant increase in heart rate and blood pressure immediately after 5-MeO-DMT administration, no other notable changes in vital parameters occurred. ECG (3 hours after administration) and safety laboratory analyses (day 7) and CADSS (days 3, 1, and 7) were unremarkable. The few adverse events reported (left-sided cramping abdominal pain and headache, both on day 0) were mild, short-lived, and resolved spontaneously by the end of the study.

Regarding the intensity of the hallucinatory experience, the recorded PES score achieved at the nominal dose of 6 mg was 17.3. This score indicated the need for a subsequent higher dose of 12 mg, as per the individualized dosing regimen design. The PES score achieved at this dose was 85.7, with a score of 75 or higher indicating the occurrence of peak hallucinatory experiences and the completion of the IDR in this patient.

Importantly, the patient reported significant improvement in depression symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and this effect was maintained over time (Table 9). Furthermore, the patient met standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score of 10 or less).

Significant improvements were observed, particularly across several MADRS items, which are outlined in Table 9. While patients' baseline scores for some items reflected the absence of symptoms (e.g., decreased appetite, difficulty concentrating, suicidal ideation), items with scores reflecting severe symptoms (e.g., decreased sleep, internal tension) showed significant improvement.

Similarly, improvements were seen in several BPRS items, including physical concerns, anxiety, emotional withdrawal, feelings of guilt, and tension.

Additionally, as outlined in Table 10, improvements in maternal function were evidenced by improvements in BIMF scores recorded on day 7, with the total score improving by 14% from 92 to 105 (out of a possible total of 120).

We also assessed several functional domains of maternal functioning, as defined by Barkin et al. Improvements in each functional domain are outlined in more detail in Table 11.

Here, significant improvements were achieved in self-care, psychosocial well-being, and management, with percentage improvements ranging from 18% (management) to 44% (self-care). These improvements strengthen the relationship between improvements in depression items and maternal functioning, as assessed by the MADRS.

It was noted that the patient had already scored relatively high before treatment. In some functional domains, scores were at or near the maximum (see Table 11), limiting the extent of improvement achieved by therapy.

Summary and Conclusion

A. An individualized dosing regimen of 6 mg of 5-MeO-DMT, followed by 12 mg of 5-MeO-DMT, administered via inhalation was well tolerated and induced a remarkable and highly significant clinical response in patients formally diagnosed with postpartum depression.

B. The clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. This rapid onset is unusual and has not been observed with conventional antidepressant classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin-reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), which typically take 4 to 6 weeks to take effect.

C. The patient experienced clinical relief within 2 hours of administration of 5-MeO-DMT, according to the IDR. This was significantly superior to any approved treatment for postpartum depression and significantly superior to any previously tested hallucinogen.

D. Although 5-MeO-DMT was administered only once and was no longer effectively excreted in the body during this period (see pharmacokinetic data in Example 6 above), a significant clinical response persisted during the 7-day follow-up period. This observation supports the excellent clinical profile of 5-MeO-DMT and allows for a convenient dosing interval.

E. In addition to the antidepressant effect, it also had a positive effect on endpoints assessing other symptoms (e.g., somatic concern, emotional alienation, anxiety, guilt, and tension), supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

F. In addition to the antidepressant effect, maternal functioning assessed using the BIMF, such as self-care, psychological well-being, and management, was also positively affected. This supports the additional benefit of 5-MeO-DMT for patients with PPD beyond improving core depressive symptoms.

The highlighted aspects show that 5-MeO-DMT, when used according to the present invention, has a significantly improved efficacy profile compared to approved pharmacological treatments for postpartum depression and all previously tested psychedelics.

These data demonstrate that the present invention addresses the technical challenges of providing improved psychoactive treatment in patients with postpartum depression with a short duration of acute hallucinogenic effects and a favorable safety profile.

A second patient with postpartum depression diagnosed by a psychiatrist participated in the clinical trial. The diagnosis was perinatal-onset major depressive disorder without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2), with onset occurring during pregnancy and within the first 4 weeks postpartum. The patient completed all scheduled visits (here, day 5 instead of day 7). The inhalation procedure was performed appropriately by the patient and was well tolerated, with no inhalation-related adverse events.

Except for a transient, clinically insignificant increase in heart rate immediately after 5-MeO-DMT administration, no other significant changes in vital parameters occurred. ECG (3 hours after administration), safety laboratory analyses (at 3 hours and on Day 7), and CADSS (at 3 hours, Day 1, and Day 7) were unremarkable. The few adverse events reported (vomiting on Day 0 and headache on Day 5) were mild, short-lived, and resolved spontaneously by the end of the study.

Regarding the intensity of the hallucinatory experience, the recorded PES score achieved at the nominal dose of 6 mg was 1. This score indicated the need for a subsequent higher dose of 12 mg administered 1 hour after the first dose, as per the design of the individualized dosing regimen. The PES score achieved for this dose was 94.7, with a score of ≥75 indicating the occurrence of the peak hallucinatory experience and the completion of the IDR in this patient.

Importantly, the patient reported significant improvement in depression symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and this effect was maintained over time. The patient also met standard criteria for MADRS response (at least a 50% improvement from baseline) and MADRS remission (a total MADRS score of 10 or less).

The second patient was breastfeeding, and breast milk samples were collected before and at various time points after the final dose, as per the clinical trial protocol. These samples were then analyzed by LC-MS/MS for the detection of 5-MeO-DMT, bufotenine (the major metabolite of 5-MeO-DMT), and 5-MIAA (the final metabolite of 5-MeO-DMT). Similar analyses were performed on the patient's serum and urine samples. The data are summarized in the table below.

These data indicate that 5-MeO-DMT was rapidly cleared from serum at the first measurement time point, 1 hour after the last dose, with the concentration of 132.9 pg/ml detected at this time point and at all subsequent time points resulting in concentrations below the lower limit of quantitation of the assay. Furthermore, endogenous levels of 5-MIAA were identified in serum before dosing, with the highest concentration detected at the first measurement time point (1 hour after dosing) and returning to baseline levels within 1 day. Urine assay data indicate the presence of 5-MeO-DMT concentrations that were approximately 4-fold higher than those detected in serum at 1 hour (indicating that significant excretion had already occurred at this time point) and rapidly declined to undetectable levels thereafter, whereas 5-MIAA levels peaked at 2.5 hours at a concentration approximately 127-fold higher than that detected in serum and then rapidly declined to endogenous levels within 7 days. Bufotenine was not detectable in urine except at 2.5 hours after dosing. Taken together, these data confirm the rapid metabolism and elimination of 5-MeO-DMT in vivo.

Analysis of breast milk samples showed no bufotenin, but 5-MeO-DMT concentrations were 2167 pg/ml at 1 hour and rapidly decreased to levels similar to those observed endogenously in serum before dosing at 8.5 hours post-dose. A similar trend was observed for 5-MIAA.

Example 13 - Clinical Trial of 5-MeO-DMT Administered Intravenously to Patients with Bipolar II Disorder - Prophetic Example

The clinical trial will enroll adult patients with bipolar II disorder and a current major depressive episode.

Patients currently taking antidepressant medications may need to stop or gradually reduce their dose over time.

Patients will receive an individualized daily 5-MeO-DMT dosing regimen via intravenous infusion. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous injectable formulation. It is understood that the dosages for 5-MeO-DMT mentioned below are based on the weight of the free base, and that the dosage for the hydrobromide salt of 5-MeO-DMT can be calculated assuming equal molar amounts are used.

Specifically, patients will receive up to three doses of 5-MeO-DMT on the dosing day (day 0): 2 mg, 5 mg, and 8 mg.

1. All patients will receive an initial dose of 2 mg of 5-MeO-DMT.

2. The second dose (5 mg) will be administered only in the following cases:

a. If the peak experience (PES total score ≥75) is not reached after the 2 mg dose, and

b. The 2 mg dose is safe and well tolerated.

3. Similarly, the third dose (8 mg) will be administered only in the following cases:

a. If the peak experience (PES total score ≥75) is not reached after the 5 mg dose, and

b. The 5 mg dose is safe and well tolerated.

Patients will be assessed for their best psychedelic experience based on the Patient Score (PES), sedation, and other endpoints described above after administration. Follow-up visits are scheduled on days 1 and 7 after administration.

Patient selection was based on the following key inclusion criteria:

1. Understand the nature of the clinical trial and provide written informed consent, signed and dated in accordance with local regulations, before performing any clinical trial-related procedures.

2. Male or female and between the ages of 18 and 64 (inclusive) at the time of screening.

3. Meet the screening criteria for bipolar II disorder and are experiencing a major depressive episode as assessed by a clinical trial psychiatrist or registered clinical psychologist.

a. Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for bipolar II disorder with a current episode of major depressive disorder, as confirmed by the Mini-International Neuropsychiatric Interview (MINI);

b. A total score of 24 or higher on the Montgomery-Osberg Depression Rating Scale (MADRS) at screening and before the first dose on Day 0;

4. A total score of 8 or less on the Young Manic Rating Scale (YMRS) at screening and before the first dose on day 0;

5. Agree not to change your psychotherapy or take any new psychoactive medications during the clinical trial period.

6. Female patients must be surgically sterilized (hysterectomy, fallopian tube ligation, or bilateral oophorectomy (within 6 months prior to screening)), postmenopausal with amenorrhea for the past 2 years, or be completely abstinent (abstaining from heterosexual sexual intercourse) or using a medically acceptable method of contraception that is highly effective (failure rate <1%), including but not limited to bilateral fallopian tube ligation/occlusion, hormonal contraceptives that suppress ovulation, or intrauterine device (including hormone-releasing intrauterine devices/systems) for 30 days prior to and 90 days after 5-MeO-DMT administration; have a negative serum pregnancy test at the time of screening; and have a negative urine pregnancy test on the day prior to screening (day -1).

7. Male patients should use preventive contraception (i.e., condoms containing spermicide or abstinence) and should not donate sperm for 30 days after receiving 5-MeO-DMT.

Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this trial:

1. Based on medical history, psychiatric evaluation, and assessment by the MINI, a current or previous diagnosis of bipolar I disorder, manic episode, psychotic disorder, major depressive disorder [MDD] or other mood disorder with psychotic features, obsessive-compulsive disorder, posttraumatic stress disorder [PTSD], autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the judgment of the investigator, would make the patient ineligible for the clinical trial.

2. Have at least one first-degree relative or first cousin with a currently diagnosed or previously diagnosed psychotic disorder, bipolar I disorder, or MDD with psychotic features.

3. (a) Suicidal ideation as specified in items 4 or 5 of the C-SSRS within the past year, during the screening period, or at baseline; or (b) suicidal behavior within the past year; or (c) a clinical assessment of significant suicide risk during a clinical interview; or (d) significant suicide risk as evidenced by non-suicidal self-harm within the past year.

4. Antidepressants were taken within 7 days or 5 times the half-life (whichever is longer) prior to administration (exception: within the last 5 weeks for fluoxetine).

5. Drugs with monoamine oxidase inhibitor (MAOI) activity were taken within 14 days or 5 half-lives (whichever is longer) prior to administration.

6. Have received mood stabilizer therapy (e.g., lamotrigine, valproic acid, atypical antipsychotics) within 14 days (28 days for lithium) or 5 half-lives (whichever is longer) prior to dosing, or are receiving mood stabilizer therapy at screening or are expected to require mood stabilizer therapy (at the investigator's discretion) during the trial.

7. In the opinion of the investigator, has previously experienced significant adverse reactions to hallucinogens or hallucinogenic drugs.

8. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

9. Any current or past clinically significant condition (e.g., severe infection, severe pulmonary disease, uncontrolled hypertension, uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)) that, in the judgment of the investigator, could interfere with the interpretation of the trial results, pose a health risk to the patient, or otherwise make the patient unsuitable for the trial.

10. Taking any medication or other substance that, in the opinion of the investigator, makes the patient unsuitable for the study.

11. Clinically significant abnormalities in physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory parameters that, in the judgment of the investigator, make the patient unsuitable for the clinical trial.

12. Female patients who have a positive pregnancy test result at the time of screening or on the day before the test (-1 day), are pregnant or breastfeeding, or plan to become pregnant during the test period and up to 30 days after 5-MeO-DMT administration.

13. Patients with a DSM-5 alcohol or drug use disorder (excluding tobacco or caffeine use disorder) within the 6 months prior to screening.

The primary objective of this trial was to determine the onset and durability of the antidepressant effects of individualized daily doses of 5-MeO-DMT 2 mg, 5 mg, and 8 mg in patients with bipolar II disorder and a current major episode of depression. Secondary objectives were to determine the effects of individualized daily doses of 5-MeO-DMT 2 mg, 5 mg, and 8 mg in patients with bipolar II disorder and a current major episode of depression on depressive symptoms and global clinical status, the safety and tolerability, the intensity and duration of the psychoactive effect [PsE], the effect on sleep quality, and the effect on cognitive outcome.

The primary endpoint of the study was the assessment of the antidepressant effect of 5-MeO-DMT as measured by change from baseline in the MADRS assessed at day 7.

Secondary endpoints include:

Antidepressant effects of 5-MeO-DMT administered via intravenous injection as assessed by:

○ Proportion of patients achieving remission (MADRS≤10) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in MADRS assessed 2 hours after final test drug administration on Day 0 and on Day 1;

○ Proportion of responders (≥50% decrease from baseline in MADRS total score) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in CGI-S 2 hours after final test drug administration on Day 0, Day 1, and Day 7;

○ Changes from baseline in BDRS on Days 1 and 7

Safety and tolerability of 5-MeO-DMT administered via injection as assessed by:

○ Reporting of treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and respiration assessments;

○ Sedation assessment (Revised Observer Assessment of Arousal and Sedation Scale [MOAA/S]) after each dose (when PsE subsides and 60 minutes after each test drug administration) and as part of the discharge assessment on Day 0;

○ Incidence of adverse events [AEs] of mania or hypomania (assessed using DSM-5 criteria for mania/hypomania);

○ Change from baseline in YMRS assessed as part of the discharge assessment on days 0, 1, and 7;

○ Change from baseline on the Clinician-Administered Dissociative State Scale (CADSS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Assessment of patient readiness for discharge at discharge on Day 0 using the Clinical Assessment of Readiness for Discharge (CADR);

○ Change from baseline on the Brief Mental State Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA).

Patients experienced PsE as reported 30 to 60 minutes after each dose when the PsE subsided:

○ PsE assessment using the Peak Experience [PE] Scale [PES] to evaluate PE achievement (PES total score ≥ 75);

○ Challenge Experience Questionnaire [CEQ];

○ Mystical Experience Questionnaire [MEQ-30];

PsE duration, defined as the time from test drug administration until PsE subsides, which is completed 30 to 60 minutes after each administration;

Impact on sleep quality as assessed by change from the day before the test (Day -1) to Days 1 and 7 on the Pittsburgh Sleep Quality Index (PSQI).

Impact on cognitive outcomes as assessed by change from the day before the test (Day -1) to discharge on Day 0, to Day 1, and to Day 7:

○ Rapid Visual Processing (RVP) Test;

○ Verbal Recognition Memory [VRM] Test;

○ Spatial working memory [SWM] test;

○ Digit symbol substitution test (DSST).

Example 14 - Clinical Trial of 5-MeO-DMT Administered by Injection to Patients with Bipolar II Disorder - Prospective Example

The clinical trial will enroll adult patients with bipolar II disorder and a current major depressive episode.

Patients currently taking antidepressant medications may need to stop or gradually reduce their dose over time.

Patients will receive an individualized daily 5-MeO-DMT dosing regimen via intravenous infusion. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous injectable formulation. It is understood that the dosages for 5-MeO-DMT mentioned below are based on the weight of the free base, and that the dosage for the hydrobromide salt of 5-MeO-DMT can be calculated assuming equal molar amounts are used.

Specifically, patients will receive up to three doses of 5-MeO-DMT on the dosing day (day 0): 1 mg, 2 mg, and 3 mg.

1. All patients will receive an initial dose of 1 mg of 5-MeO-DMT.

2. The second dose (2 mg) will be administered only in the following cases:

a. If the peak experience (PES total score ≥75) is not reached after the 1 mg dose, and

b. The 1 mg dose is safe and well tolerated.

3. Similarly, the third dose (3 mg) will be administered only in the following cases:

a. If the peak experience (PES total score ≥75) is not reached after the 2 mg dose, and

b. The 2 mg dose is safe and well tolerated.

Patients will be assessed for their best psychedelic experience based on the Patient Score (PES), sedation, and other endpoints described above after administration. Follow-up visits are scheduled on days 1 and 7 after administration.

Patient selection was based on the following key inclusion criteria:

1. Understand the nature of the clinical trial and provide written informed consent, signed and dated in accordance with local regulations, before performing any clinical trial-related procedures.

2. Male or female and between the ages of 18 and 64 (inclusive) at the time of screening.

3. Meet the screening criteria for bipolar II disorder and are experiencing a major depressive episode as assessed by a clinical trial psychiatrist or registered clinical psychologist.

a. Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for bipolar II disorder with a current episode of major depressive disorder, as confirmed by the Mini-International Neuropsychiatric Interview (MINI);

b. A total score of 24 or higher on the Montgomery-Osberg Depression Rating Scale (MADRS) at screening and before the first dose on Day 0;

4. A total score of 8 or less on the Young Manic Rating Scale (YMRS) at screening and before the first dose on day 0;

5. Agree not to change your psychotherapy or take any new psychoactive medications during the clinical trial period.

6. Female patients must be surgically sterilized (hysterectomy, fallopian tube ligation, or bilateral oophorectomy (within 6 months prior to screening)), postmenopausal with amenorrhea for the past 2 years, or be completely abstinent (abstaining from heterosexual sexual intercourse) or using a medically acceptable method of contraception that is highly effective (failure rate <1%), including but not limited to bilateral fallopian tube ligation/occlusion, hormonal contraceptives that suppress ovulation, or intrauterine device (including hormone-releasing intrauterine devices/systems) for 30 days prior to and 90 days after 5-MeO-DMT administration; have a negative serum pregnancy test at the time of screening; and have a negative urine pregnancy test on the day prior to screening (day -1).

7. Male patients should use preventive contraception (i.e., condoms containing spermicide or abstinence) and should not donate sperm for 30 days after receiving 5-MeO-DMT.

Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this trial:

1. Based on medical history, psychiatric evaluation, and assessment by the MINI, a current or previous diagnosis of bipolar I disorder, manic episode, psychotic disorder, major depressive disorder [MDD] or other mood disorder with psychotic features, obsessive-compulsive disorder, posttraumatic stress disorder [PTSD], autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the judgment of the investigator, would make the patient ineligible for the clinical trial.

2. Have at least one first-degree relative or first cousin with a currently diagnosed or previously diagnosed psychotic disorder, bipolar I disorder, or MDD with psychotic features.

3. (a) Suicidal ideation as specified in items 4 or 5 of the C-SSRS within the past year, during the screening period, or at baseline; or (b) suicidal behavior within the past year; or (c) a clinical assessment of significant suicide risk during a clinical interview; or (d) significant suicide risk as evidenced by non-suicidal self-harm within the past year.

4. Antidepressants were taken within 7 days or 5 times the half-life (whichever is longer) prior to administration (exception: within the last 5 weeks for fluoxetine).

5. Drugs with monoamine oxidase inhibitor (MAOI) activity were taken within 14 days or 5 half-lives (whichever is longer) prior to administration.

6. Have received mood stabilizer therapy (e.g., lamotrigine, valproic acid, atypical antipsychotics) within 14 days (28 days for lithium) or 5 half-lives (whichever is longer) prior to dosing, or are receiving mood stabilizer therapy at screening or are expected to require mood stabilizer therapy (at the investigator's discretion) during the trial.

7. In the opinion of the investigator, has previously experienced a serious adverse reaction to hallucinogens or hallucinogenic drugs.

8. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

9. Any current or past clinically significant condition (e.g., severe infection, severe pulmonary disease, uncontrolled hypertension, uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)) that, in the judgment of the investigator, could interfere with the interpretation of the trial results, pose a health risk to the patient, or otherwise make the patient unsuitable for the trial.

10. Taking any medication or other substance that, in the opinion of the investigator, makes the patient unsuitable for the study.

11. Clinically significant abnormalities in physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory parameters that, in the judgment of the investigator, make the patient unsuitable for the clinical trial.

12. Female patients who have a positive pregnancy test result at the time of screening or on the day before the test (-1 day), are pregnant or breastfeeding, or plan to become pregnant during the test period and up to 30 days after 5-MeO-DMT administration.

13. Patients with a DSM-5 alcohol or drug use disorder (excluding tobacco or caffeine use disorder) within the 6 months prior to screening.

The primary objective of this trial was to determine the onset and durability of the antidepressant effects of individualized daily doses of 5-MeO-DMT 1 mg, 2 mg, and 3 mg in patients with bipolar II disorder and a current major episode of depression. Secondary objectives were to determine the effects of individualized daily doses of 5-MeO-DMT 1 mg, 2 mg, and 3 mg in patients with bipolar II disorder and a current major episode of depression on depressive symptoms and global clinical status, the safety and tolerability, the intensity and duration of the psychoactive effect [PsE], the effect on sleep quality, and the effect on cognitive outcome.

The primary endpoint of the study was the assessment of the antidepressant effect of 5-MeO-DMT as measured by change from baseline in the MADRS assessed at day 7.

Secondary endpoints include:

Antidepressant effects of 5-MeO-DMT administered via intravenous injection as assessed by:

○ Proportion of patients achieving remission (MADRS≤10) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in MADRS assessed 2 hours after final test drug administration on Day 0 and on Day 1;

○ Proportion of responders (≥50% decrease from baseline in MADRS total score) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in CGI-S 2 hours after final test drug administration on Day 0, Day 1, and Day 7;

○ Changes from baseline in BDRS on Days 1 and 7

Safety and tolerability of 5-MeO-DMT administered via injection as assessed by:

○ Reporting of treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and respiration assessments;

○ Sedation assessment (Revised Observer Assessment of Arousal and Sedation Scale [MOAA/S]) after each dose (when PsE subsides and 60 minutes after each test drug administration) and as part of the discharge assessment on Day 0;

○ Incidence of adverse events [AEs] of mania or hypomania (assessed using DSM-5 criteria for mania/hypomania);

○ Change from baseline in YMRS assessed as part of the discharge assessment on days 0, 1, and 7;

○ Change from baseline on the Clinician-Administered Dissociative State Scale (CADSS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Assessment of patient readiness for discharge at discharge on Day 0 using the Clinical Assessment of Readiness for Discharge (CADR);

○ Change from baseline on the Brief Mental State Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA).

Patients experienced PsE as reported 30 to 60 minutes after each dose when the PsE subsided:

○ PsE assessment using the Peak Experience [PE] Scale [PES] to evaluate PE achievement (PES total score ≥ 75);

○ Challenge Experience Questionnaire [CEQ];

○ Mystical Experience Questionnaire [MEQ-30];

PsE duration, defined as the time from test drug administration until PsE subsides, which is completed 30 to 60 minutes after each administration;

Impact on sleep quality as assessed by change from the day before the test (Day -1) to Days 1 and 7 on the Pittsburgh Sleep Quality Index (PSQI).

Impact on cognitive outcomes as assessed by change from the day before the test (Day -1) to discharge on Day 0, to Day 1, and to Day 7:

○ Rapid Visual Processing (RVP) Test;

○ Verbal Recognition Memory [VRM] Test;

○ Spatial working memory [SWM] test;

○ Digit symbol substitution test (DSST).

Example 15 - Clinical Trial of 5-MeO-DMT Administered Intravenously to Patients with Postpartum Depression - Prophetic Example

The clinical trial will include adult female patients with clinically diagnosed postpartum depression (PPD).

Patients will receive a single-day, individualized 5-MeO-DMT dosing regimen via intravenous infusion. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous formulation. It is understood that the dosages for 5-MeO-DMT mentioned below are based on the weight of the free base, and that the dosage for the hydrobromide salt of 5-MeO-DMT can be calculated assuming equimolar amounts.

More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0: 2 mg, 5 mg, and 8 mg.

1. All patients will receive an initial dose of 2 mg of 5-MeO-DMT.

2. The second dose (5 mg) will be administered only in the following cases:

a. If the peak experience (total score ≥75) is not achieved after the 2 mg dose;

b. If the 2 mg dose is deemed safe and well tolerated by the investigator,

c. If any psychoactive effect (PsE) of the previous dose has subsided,

d. If pre-administration vital parameters and forced expiratory volume in 1 second [FEV1] are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

3. Similarly, the third dose (8 mg) will be administered only in the following cases:

a. If the peak experience (total score ≥75) is not achieved after the 5 mg dose, and

b. If the 5 mg dose is deemed safe and well tolerated by the investigator,

c. If any PsE from the previous volume has settled,

d. If pre-administration vital parameters and forced expiratory volume in 1 second [FEV1] are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

Patients will be evaluated for peak hallucination experience (based on the Patient Rating Visual Analog Scale, PE scale), sedation, and other endpoints after administration. Follow-up visits are scheduled on days 1 and 7 after administration.

All patients considered for participation in a clinical trial must meet the following criteria:

1. Female and between the ages of 18 and 45 (inclusive) at the time of screening.

2. Body mass index [BMI] at screening is in the range of 18.5 and 35 kg/m ² (inclusive).

3. Meets the testing criteria for PPD as assessed by a clinical trial psychiatrist or registered psychologist.

a. Diagnosis of major depressive disorder without psychotic features, with perinatal onset, beginning after pregnancy and within the first 4 weeks postpartum, as confirmed by the Mini International Neuropsychiatric Interview (MINI).

b. A total score of 28 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS) at screening and before administration on Day 0.

6. You must have stopped breastfeeding at the time of screening, or if you are breastfeeding or breastfeeding at the time of screening, you must temporarily stop breastfeeding from immediately before the study drug dose on Day 0 until 24 hours after the last dose, and if necessary, express and discard all breast milk during that 24-hour period, but agree that you will need to include expressing/discarding milk 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding.

4. Patients must agree to complete abstinence (abstaining from heterosexual intercourse) or use a medically accepted method of contraception with a highly effective (failure rate of <1%) method for 30 days before and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test result at screening and on the day before (Day -1).

5. Willing to delay starting any other antidepressant or anxiety medication until after the trial ends on Day 7 and agree not to change any psychotherapy during the trial.

Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this trial:

1. Based on medical history, psychiatric evaluation, and MINI assessment, a current or past diagnosis of bipolar disorder, manic or hypomanic episode, psychotic disorder, major depressive disorder [MDD] or other mood disorder with psychotic features, obsessive-compulsive disorder, posttraumatic stress disorder [PTSD], autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient ineligible for the study.

2. If you have one or more first- or second-degree relatives who currently or in the past have bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

3. Significant suicide risk, as judged by a clinical psychiatrist or registered psychologist, based on medical history, psychiatric evaluation, and assessment of suicidal ideation and suicidal behavior using the Columbia Suicide Severity Rating Scale (C-SSRS).

4. Antidepressants were taken within 14 days or 5 times the half-life (whichever is longer) prior to the dose (exception: within the last 5 weeks for fluoxetine).

5. Any other drug with monoamine oxidase inhibitor (MAOI) activity was taken within 14 days or 5 half-lives (whichever is longer) prior to administration.

6. Previous serious adverse reactions to hallucinogens or psychedelic drugs (e.g., psilocybin, psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), as determined by the investigator.

7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

8. Any current or past clinically significant condition that, in the judgment of the investigator, would make the patient ineligible for the study [e.g., severe infection, pulmonary disease, uncontrolled hypertension, new-onset gestational hypertensive disorder during pregnancy or the postpartum period (e.g., gestational hypertension, pre-eclampsia-eclampsia, superimposed pre-eclampsia), uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)].

9. Administer any medication or other substance that, in the judgment of the investigator, makes the patient unsuitable for the study.

10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that, in the judgment of the investigator, make the patient unsuitable for the clinical trial.

11. Patients who have a positive pregnancy test at screening or on the day before screening (-1), are pregnant, or plan to become pregnant during the clinical trial and up to 90 days after 5-MeO-DMT administration.

12. Patients with a DSM-5 drug or alcohol use disorder within the 6 months prior to screening.

The primary objective of this trial was to determine the onset and 7-day durability of the antidepressant effect of single-day individualized dosing regimens of 2 mg, 5 mg, and 8 mg of 5-MeO-DMT in adult female patients with PPD.

Secondary objectives were to determine the antidepressant effects; anxiolytic effects; effects on maternal behavior; safety and tolerability; magnitude and duration of psychotropic effects (PsE); and effects on cognitive outcomes of single-day individualized dosing regimens of 2 mg, 5 mg, and 8 mg of 5-MeO-DMT in adult female patients with PPD.

The exploratory objective was to determine the amounts of 5-MeO-DMT and its metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA), in breast milk, blood, and urine, as measured by LC/MS/MS, following single-day IDR doses of 2 mg, 5 mg, and 8 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identification screening can be performed as needed).

The primary endpoint of the study was the assessment of the antidepressant effect of 5-MeO-DMT as measured by change from baseline in the MADRS assessed at day 7.

Secondary endpoints included the antidepressant effect of 5-MeO-DMT, assessed as follows:

The antidepressant effects of 5-MeO-DMT are evaluated by:

○ Proportion of patients achieving remission (MADRS≤10) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in MADRS assessed 2 hours after final test drug administration on Day 0 and on Day 1;

○ Proportion of responders (≥50% decrease from baseline in MADRS total score) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Clinical Global Impression Severity Scale [CGI-S] 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

Effects on maternal behavior as assessed by changes from baseline in the Barkin Maternal Function Index (BIMF) total and subscale scores by day 7;

Exposure to 5-MeO-DMT and bufotenine in breast milk obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, in the evening of day 0, and on days 1 and 7;

Exposure of 5-MeO-DMT and bufotenine in blood obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, and on days 1 and 7;

The safety and tolerability of 5-MeO-DMT were evaluated as follows.

○ Reporting of treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak flow apnea measurements;

○ Sedation assessment (Revised Observer Assessment of Arousal and Sedation Scale [MOAA/S]) after each dose (when PsE subsides and 60 minutes after each test drug administration) and as part of the discharge assessment on Day 0;

○ Change from baseline on the Clinician-Administered Dissociative State Scale (CADSS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline on the Brief Mental State Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline in the C-SSRS assessed as part of the discharge assessment on days 0, 1, and 7;

○ Change from baseline in YMRS assessed as part of the discharge assessment on days 0, 1, and 7;

Patients experienced PsE as reported 30 to 60 minutes after each dose when the PsE subsided:

○ PsE assessment using the Peak Experience [PE] scale to evaluate PE achievement (PE scale total score ≥ 75);

○ Challenge Experience Questionnaire [CEQ];

○ Mystical Experience Questionnaire [MEQ-30];

Duration of PsE, defined as the time from test drug administration until PsE subsides (scores by investigator and patient), is completed 30 to 60 minutes after each dose.

Example 16 - Clinical Trial of 5-MeO-DMT Administered Intravenously to Patients with Postpartum Depression - Prophetic Example

The clinical trial will include adult female patients with clinically diagnosed postpartum depression (PPD).

Patients will receive a single-day, individualized 5-MeO-DMT dosing regimen via intravenous infusion. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous formulation. It is understood that the dosages for 5-MeO-DMT mentioned below are based on the weight of the free base, and that the dosage for the hydrobromide salt of 5-MeO-DMT can be calculated assuming equimolar amounts.

More specifically, patients will receive up to three sessions of 1 mg, 2 mg, and 3 mg of 5-MeO-DMT on day 0.

1. All patients will receive an initial dose of 1 mg of 5-MeO-DMT.

2. The second dose (2 mg) will be administered only in the following cases:

a. If the best experience (total score ≥75) is not achieved after the 1 mg dose;

b. If the 1 mg dose is safe and well tolerated according to the investigator's judgment,

c. If any psychoactive effect (PsE) of the previous dose has subsided,

d. If pre-administration vital parameters and forced expiratory volume in 1 second [FEV1] are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

3. Similarly, the third dose (3 mg) will be administered only in the following cases:

a. If the peak experience (total score ≥75) is not achieved after the 2 mg dose;

b. If the 2 mg dose is deemed safe and well tolerated by the investigator,

c. If any PsE from the previous volume has settled,

d. If pre-administration vital parameters and forced expiratory volume in 1 second [FEV1] are within the normal range, or if they are outside the normal range but are not clinically significant according to the investigator's judgment.

Patients will be evaluated for peak hallucination experience (based on the Patient Rating Visual Analog Scale, PE scale), sedation, and other endpoints after administration. Follow-up visits are scheduled on days 1 and 7 after administration.

All patients considered for participation in a clinical trial must meet the following criteria:

1. Female and between the ages of 18 and 45 (inclusive) at the time of screening.

2. Body mass index [BMI] at screening is in the range of 18.5 and 35 kg/m ² (inclusive).

3. Meets the testing criteria for PPD as assessed by a clinical trial psychiatrist or registered psychologist.

a. Diagnosis of major depressive disorder without psychotic features, with perinatal onset, beginning after pregnancy and within the first 4 weeks postpartum, as confirmed by the Mini International Neuropsychiatric Interview (MINI).

b. A total score of 28 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS) at screening and before administration on Day 0.

6. You must have stopped breastfeeding at the time of screening, or if you are breastfeeding or breastfeeding at the time of screening, you must temporarily stop breastfeeding from immediately before the study drug dose on Day 0 until 24 hours after the last dose, and if necessary, express and discard all breast milk during that 24-hour period, but agree that you will need to include expressing/discarding milk 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding.

4. Patients must agree to complete abstinence (abstaining from heterosexual intercourse) or use a medically accepted method of contraception with a highly effective (failure rate of <1%) method for 30 days before and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test result at screening and on the day before (Day -1).

5. Willing to delay starting any other antidepressant or anxiety medication until after the trial ends on Day 7 and agree not to change any psychotherapy during the trial.

Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this trial:

1. Based on medical history, psychiatric evaluation, and MINI assessment, a current or past diagnosis of bipolar disorder, manic or hypomanic episode, psychotic disorder, major depressive disorder [MDD] or other mood disorder with psychotic features, obsessive-compulsive disorder, posttraumatic stress disorder [PTSD], autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient ineligible for the study.

2. If you have one or more first- or second-degree relatives who currently or in the past have bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

3. Significant risk of suicide, as determined by a clinical psychiatrist or registered psychologist, based on medical history, psychiatric evaluation, and assessment of suicidal ideation and suicidal behavior using the Columbia Suicide Severity Rating Scale (C-SSRS).

4. Antidepressants were taken within 14 days or 5 times the half-life (whichever is longer) prior to the dose (exception: within the last 5 weeks for fluoxetine).

5. Any other drug with monoamine oxidase inhibitor (MAOI) activity was taken within 14 days or 5 half-lives (whichever is longer) prior to administration.

6. Previous serious adverse reactions to hallucinogens or psychedelic drugs (e.g., psilocybin, psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), as determined by the investigator.

7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

8. Any current or past clinically significant condition that, in the judgment of the investigator, would make the patient ineligible for the study [e.g., severe infection, pulmonary disease, uncontrolled hypertension, new-onset gestational hypertensive disorder during pregnancy or the postpartum period (e.g., gestational hypertension, pre-eclampsia-eclampsia, superimposed pre-eclampsia), uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)].

9. Administer any medication or other substance that, in the judgment of the investigator, makes the patient unsuitable for the study.

10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that, in the judgment of the investigator, make the patient unsuitable for the clinical trial.

11. Patients who have a positive pregnancy test at screening or on the day before screening (-1 day), are pregnant, or plan to become pregnant during the clinical trial and up to 90 days after 5-MeO-DMT administration.

12. Patients with a DSM-5 drug or alcohol use disorder within the 6 months prior to screening.

The primary objective of this trial was to determine the onset and 7-day durability of the antidepressant effect of single-day individualized dosing regimens of 1 mg, 2 mg, and 3 mg of 5-MeO-DMT in adult female patients with PPD.

Secondary objectives were to determine the antidepressant effects; anxiolytic effects; effects on maternal behavior; safety and tolerability; magnitude and duration of psychotropic effects (PsE); and effects on cognitive outcomes of single-day individualized dosing regimens of 1 mg, 2 mg, and 3 mg of 5-MeO-DMT in adult female patients with PPD.

The exploratory objective was to determine the amounts of 5-MeO-DMT and its metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA), in breast milk, blood, and urine, as measured by LC/MS/MS, following single-day IDR doses of 1 mg, 2 mg, and 3 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identification screening can be performed as needed).

The primary endpoint of the study was the assessment of the antidepressant effect of 5-MeO-DMT as measured by change from baseline in the MADRS assessed at day 7.

Secondary endpoints included the antidepressant effect of 5-MeO-DMT, assessed as follows:

The antidepressant effects of 5-MeO-DMT are evaluated by:

○ Proportion of patients achieving remission (MADRS≤10) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Change from baseline in MADRS assessed 2 hours after final test drug administration on Day 0 and on Day 1;

○ Proportion of responders (≥50% decrease from baseline in MADRS total score) 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

○ Clinical Global Impression Severity Scale [CGI-S] 2 hours after the final test drug administration on Day 0 and on Days 1 and 7;

Effects on maternal behavior as assessed by changes from baseline in the Barkin Maternal Function Index (BIMF) total and subscale scores by day 7;

Exposure to 5-MeO-DMT and bufotenine in breast milk obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, in the evening of day 0, and on days 1 and 7;

Exposure of 5-MeO-DMT and bufotenine in blood obtained on the day before the test (day -1), 1 hour after the last test drug administration, at discharge, and on days 1 and 7;

The safety and tolerability of 5-MeO-DMT were evaluated as follows.

○ Reporting of treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak flow apnea measurements;

○ Sedation assessment (Revised Observer Assessment of Arousal and Sedation Scale [MOAA/S]) after each dose (when PsE subsides and 60 minutes after each test drug administration) and as part of the discharge assessment on Day 0;

○ Change from baseline on the Clinician-Administered Dissociative State Scale (CADSS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline on the Brief Mental State Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and on Days 1 and 7;

○ Change from baseline in the C-SSRS assessed as part of the discharge assessment on days 0, 1, and 7;

○ Change from baseline in YMRS assessed as part of the discharge assessment on days 0, 1, and 7;

Patients experienced PsE as reported 30 to 60 minutes after each dose when the PsE subsided:

○ PsE assessment using the Peak Experience [PE] scale to evaluate PE achievement (PE scale total score ≥ 75);

○ Challenge Experience Questionnaire [CEQ];

○ Mystical Experience Questionnaire [MEQ-30];

Duration of PsE defined as the time from study drug administration to PsE subsidence (investigator- and patient-scored), completed 30 to 60 minutes after each dose.

Claims (87)

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of mental or nervous disorders in lactating women,
A dose of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt is administered as a single dose or as the highest dose in an uptitration scheme with an interval between doses of at least about 1 hour,
The above 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous route,
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in which case temporary discontinuation of breastfeeding is recommended in the above patient. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the patient is advised to temporarily discontinue breastfeeding at least 1 hour before receiving the first dose and to resume breastfeeding at least 24 hours after the last dose. In the first aspect, the patient is advised to temporarily discontinue breastfeeding at least 1 hour before receiving the first dose and to resume breastfeeding at least 12 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding at least 1 hour before receiving the first dose and to resume breastfeeding at least 6 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the patient is advised to temporarily discontinue breastfeeding at least 1 hour before receiving the first dose and to resume breastfeeding at least 2 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the patient is advised to temporarily discontinue breastfeeding at least 1 hour before receiving the first dose and to resume breastfeeding at least 1 hour after the last dose. In the first aspect, the patient is advised to temporarily discontinue breastfeeding immediately before receiving the first dose and to resume breastfeeding at least 24 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding immediately before receiving the first dose and to resume breastfeeding at least 12 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding immediately before receiving the first dose and to resume breastfeeding at least 6 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding immediately before receiving the first dose and to resume breastfeeding at least 2 hours after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding immediately before receiving the first dose and to resume breastfeeding at least 1 hour after the last dose, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. In the first aspect, the patient is advised to temporarily discontinue breastfeeding only during the actual treatment period, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the patient is advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until ready for discharge, in any one of claims 1 to 12. In paragraph 13, the decision to prepare for discharge occurs about 1 hour after the last administration of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in claim 13 or 14, wherein the patient is advised not to resume breastfeeding before the later of discharge and 6 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein the patient is advised not to resume breastfeeding before the later of discharge and 3 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein the patient is advised not to resume breastfeeding before the later of discharge and 2 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 15, wherein the patient is advised not to resume breastfeeding before the later of discharge and 1 hour after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in any one of claims 1 to 18, wherein the patient is advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until at least 24 hours after the last dose and to discard all breast milk expressed during the 24-hour period. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in any one of claims 1 to 18, wherein the patient is advised to temporarily discontinue breastfeeding from immediately before receiving the first dose until at least 2.5 hours after the last dose and to express and discard breast milk 2.5 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 20, wherein the patient is advised to express and discard breast milk 24 hours after the last dose before resuming breastfeeding. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 21, wherein the patient is advised to breastfeed the child no more than twice during the first 12 hours after the last dose. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 22, wherein any expressed breast milk is discarded as long as the concentration of 5-MeO-DMT and/or 5-MIAA in the breast milk exceeds a predetermined threshold. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 2000 pg in claim 23. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 500 pg in claim 23. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 75 pg in claim 23. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 14000 pg, in any one of claims 23 to 26. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 2000 pg, in any one of claims 23 to 26. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 75 pg, in any one of claims 23 to 26. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is resumed when the concentration of 5-MeO-DMT and/or the concentration of 5-MIAA in breast milk is below a predetermined threshold, according to any one of claims 1 to 22. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 2000 pg in claim 30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 500 pg in claim 30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MeO-DMT is 75 pg in claim 30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 14000 pg, in any one of claims 30 to 33. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 2000 pg, in any one of claims 30 to 33. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the threshold for 5-MIAA is 75 pg, in any one of claims 30 to 33. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is configured such that the DID of 5-MeO-DMT per 1 kg of infant body weight is less than or equal to 1 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein said configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is configured such that the DID of 5-MeO-DMT per kg of infant body weight is less than or equal to 0.4 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is configured such that the DID of 5-MeO-DMT per kg of infant body weight is less than or equal to 0.2 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 10% or less during the first 24 hours after resumption of breastfeeding, wherein said configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in any one of claims 1 to 39, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 5% or less during the first 24 hours after resumption of breastfeeding, wherein said configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein breastfeeding is configured such that the RID of 5-MeO-DMT is 1% or less during the first 24 hours after resumption of breastfeeding, wherein said configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the breastfeeding is configured such that the DID of the final metabolite 5-MIAA per kg of infant body weight is less than or equal to 4 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the breastfeeding is configured such that the DID of the final metabolite 5-MIAA per 1 kg of infant body weight is less than or equal to 2 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the breastfeeding is configured such that the DID of the final metabolite 5-MIAA per 1 kg of infant body weight is less than or equal to 1 μg/kg/day during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in any one of claims 1 to 45, wherein breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 4% or less during the first 24 hours after resumption of breastfeeding, wherein said configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 2% or less during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the breastfeeding is configured such that the RID of the final metabolite 5-MIAA is 1% or less during the first 24 hours after resumption of breastfeeding, wherein the configuration is selected by an appropriate time for resumption of breastfeeding, an appropriate number of feedings during the first 24 hours after resumption of breastfeeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 48, wherein the patient suffers from PPD. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein, in claim 49, relief of depressive symptoms, as assessed by a MADRS score of 10 or less, occurs within about 2 hours after the last administration of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein, in claim 50, relief of depressive symptoms, as assessed by a HAM-D score of 7 or less, occurs within about 2 hours after the last administration of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein maternal function is improved as reflected by improvement in the functional domain of the Barkin Index of Maternal Functioning (BIMF) of maternal interaction and psychological well-being according to any one of claims 1 to 51. In claim 52, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the improvement in the cumulative score of the BIMF scale item reflecting psychological well-being is at least 25%, and the improvement in the cumulative score of the BIMF scale item responding to mother-child interaction is at least 5%. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein, in claim 52 or 53, improvement in the MADRS items of boredom, pessimistic thinking, apathy, internal tension and/or reduced sleep leads to an increase in the BIMF scale score reflecting psychosocial well-being, and improvement in the MADRS items of apathy and internal tension leads to an increase in the BIMF scale score reflecting mother-child interaction. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the patient suffers from a mental or neurological disorder comprising one or more symptoms selected from sleep disturbance and anxiety, each of which impairs maternal function, according to any one of claims 1 to 54. In claim 55, the patient suffers from a mental or nervous disorder including anxiety symptoms, wherein the treatment is 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduces or eliminates anxiety symptoms, particularly those of internal tension. In claim 56, the treatment leads to a clinical response as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score prior to treatment, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In claim 56 or 57, the treatment leads to a clinical response as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score prior to treatment, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof on day 1. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the treatment in any one of claims 56 to 58 results in a clinical response as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score prior to treatment, at about 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the treatment in any one of claims 56 to 59 results in a clinical response as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score prior to treatment, at about 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the treatment in any one of claims 56 to 60 results in a clinical response as reflected by a decrease in the HAM-A score of at least 50% compared to the respective score prior to treatment, at about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In any one of claims 55 to 61, wherein the patient suffers from a mental or neurological disorder including symptoms of sleep disorder, and the treatment is 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which reduces or eliminates symptoms of sleep disorder. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the patient suffers from sleep disturbance as reflected by a Pittsburgh Sleep Quality Index (PSQI) overall score of greater than 5 in claim 62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, in claim 62 or 63, wherein the treatment reduces or eliminates sleep disturbance, and the reduction or elimination of sleep disturbance is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 1, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period is from the time when the acute hallucinatory experience after the last administration subsides to the time of assessment. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the treatment success is indicated by a decrease in the PSQI overall score in any one of claims 62 to 64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, in any one of claims 62 to 65, wherein the treatment success is indicated by a decrease in at least four of the seven components of PSQI. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, in any one of claims 62 to 66, wherein the treatment success is indicated by a decrease in the PSQI overall score to 5 points or less. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, according to any one of claims 62 to 67, wherein the sleep disorder is insomnia. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT or a salt thereof is administered in a dose or dosage regimen that provides the patient with the best hallucinogenic experience. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT, in any one of claims 1 to 69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a dosage of about 1 mg; or about 2 mg; or about 3 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT, according to any one of claims 1 to 69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a dosage of about 2 mg; or about 4 mg; or about 6 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt is administered instead of 5-MeO-DMT, in any one of claims 1 to 69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 69, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose and for the first administration; 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration unless the patient experiences the highest psychedelic experience. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT is administered in a dosage of about 1 mg to about 3 mg for the first administration, and is increased to a dosage of about 4 mg to about 6 mg for the second administration, unless the patient has already experienced a peak hallucinatory experience, and is increased to a dosage of about 7 mg to about 9 mg for the third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. In claim 74, the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT is administered in a dosage of about 0.5 mg to about 1.5 mg for the first administration, and is increased to a dosage of about 1.5 mg to about 2.5 mg for the second administration, unless the patient has already experienced a peak hallucinatory experience, and is increased to a dosage of about 2.5 mg to about 3.5 mg for the third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. In claim 76, the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT is administered in a dosage of about 2 mg to about 3 mg for the first administration, and is increased to a dosage of about 4 mg to about 5 mg for the second administration, unless the patient has already experienced a peak hallucinatory experience, and is increased to a dosage of about 6 mg to about 7.5 mg for the third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. In claim 78, the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 4 mg, and the third dose of 5-MeO-DMT is about 6 mg; or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, according to any one of claims 73 to 79, wherein the interval between two administrations is at least 1 hour and no more than 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours. In any one of Articles 1 to 69,
A dose of about 1 mg to about 5 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt is administered as a single dose or as the highest dose in a dose escalation schedule with an interval between doses of at least about 1 hour,
The above 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous route,
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, in which case temporary discontinuation of breastfeeding is recommended in the above patient. In claim 81, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein a dosage of about 1 mg; or about 5 mg is administered, or an equimolar amount of a pharmaceutically acceptable salt thereof is administered instead of 5-MeO-DMT. In claim 82, 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose and for the first administration; 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in 0 to 6 subsequent administrations; and each subsequent administration uses a higher dose than the previous administration unless the patient experiences the highest psychedelic experience. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the interval between two administrations is at least 1 hour and no more than 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, in any one of claims 69 to 84, wherein the occurrence of said peak hallucinatory experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales (Mystical, Positive Mood, Transcendence of Time and Space, and Ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75. In claim 85, the occurrence of a peak hallucinatory experience is confirmed by achieving a peak experience scale [PES] total score of at least 75, 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 5-MeO-DMT or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 86, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.