CN118973568A - Treatment of mental disorders - Google Patents

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a psychiatric or neurological disorder in a mother with a child 18 months or younger.

Description

Treatment of mental disorders

Technical Field

The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating maternal patients diagnosed with mental or nervous system disorders, particularly breastfeeding mother patients.

The psychiatric disorder is amenable to treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The treatment also improves maternal function.

Furthermore, the present invention allows for the treatment of psychiatric or neurological disorders in breastfeeding mothers without requiring near-total interruption of breastfeeding.

Background Art

Mental or neurological disorders in breastfeeding mothers can have a range of negative consequences for the mother, her baby, and her family. For example, women with mental or neurological disorders may have thoughts of harming themselves or their children, and they are at increased risk of suicide.

Mental or neurological disorders may further contribute to disrupted interactions between mother and child, as exemplified by higher rates of disengagement behaviors and lower rates of visual and vocal communication between mother and child. Evidence also suggests a link between maternal mental or neurological disorders and child development, as suggested by the fact that children of patients with mental or neurological disorders may be at greater risk of impaired cognitive development.

Despite these problems, treatment options remain limited. In general, known treatments for psychiatric or neurological disorders often have limited success rates, particularly for patients who experience more than mild symptoms of the disorder.

A complicating factor in cases where the patient is a breastfeeding mother is that for many drugs, breastfeeding women are advised to discontinue breastfeeding while taking the drug and for a period of time thereafter because the drug may be excreted in breast milk, placing the unweaned child at risk.

Additionally, research suggests that breastfeeding mothers may be reluctant to start medication due to a range of concerns.

Therefore, breastfeeding patients with psychiatric or neurological disorders may be faced with the situation where they must decide whether to stop breastfeeding or discontinue/forgo treatment.

Against this background, there is a need for improved treatments of mental or neurological disorders, particularly treatments that not only effectively address the symptoms of the disorder and rapidly produce a clinical response, but also avoid interfering with the patient's daily activities, particularly with regard to the care of the infant. The treatment should improve maternal function. In addition, there is a need for a treatment of mental or neurological disorders that does not require almost complete interruption of breastfeeding.

Despite recent interest in the use of hallucinogens to treat psychiatric disorders, treatments based on these substances have not been conducted in breastfeeding mothers to date. This is due to a general lack of clinical data to draw conclusions about the clinical utility of hallucinogens and to concerns that their administration may not be appropriate for breastfeeding mothers.

Hallucinogens (including psychedelics) are chemical compounds, some naturally occurring and some synthetic, that are defined as being able to induce sensory distortions, such as changes in auditory and visual perception, as well as distortions of mood and cognition, when taken by a person. The term hallucinogen covers a fairly broad group of psychoactive molecules with different modes of action. Some psychiatric disorders are in principle considered amenable to treatment with psychoactive molecules such as psychedelics.

However, no psychedelic drug has yet been approved by any regulatory agency. In fact, clinical experience with such molecules is still quite limited.

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

In this context, it is an object of the present invention in particular to provide a therapy that is more effective than previously described therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) a clinical response occurs earlier, and/or d) a clinical response is more durable).

It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, which have better safety and/or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, which are more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, which are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that benefit from such improved psychoactive therapies.

It is a still further object of the present invention to improve maternal function in patients suffering from psychiatric or neurological disorders, particularly breastfeeding mothers diagnosed with psychiatric disorders.

Summary of the invention

The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating mothers diagnosed with mental or nervous system disorders, particularly breastfeeding mothers diagnosed with such disorders. The disorder may in particular be a disorder characterized by depressive episodes, such as major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias and substance/medication-induced anxiety disorders; somatic symptom disorder; obsessive-compulsive disorder 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 migraine; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; mental disorders or neurological disorders associated with HIV, COVID sequelae or traumatic brain injury.

In one aspect, the patient may suffer from a sleep disorder.

Treatment can improve maternal functioning.

Patients to be treated are particularly breastfeeding mothers.

The present invention also allows for treatment of breastfeeding mothers without requiring near-total interruption of breastfeeding.

The present invention also provides dosage ranges and administration regimens that can be used for the above-mentioned treatments.

DETAILED DESCRIPTION

definition

As used in the context of the present invention, unless otherwise indicated, 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 acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. Assuming that equimolar amounts are used, the appropriate weight of the salt to be administered can be calculated based on the weight of the free base.

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

For example, the diagnosis of mental disorder or nervous system disorder can be carried out according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) issued by the American Psychiatric Association. In some cases, as apparent from the discussion of specific circumstances below, it is possible to modify or supplement the standard to better define a patient or patient population that is particularly benefited from treatment according to the present invention. In any case, the diagnosis will be carried out by a doctor or psychologist. It is not enough for the human subject himself to believe that he suffers from the disorder.

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

The patient may suffer from a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. The patient has not adequately improved after at least two adequate courses of treatment, in particular, at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy. In particular, at least two prior courses of treatment were administered during the current episode of the disease, for example, if the patient suffers from a disorder characterized by a depressive episode, during the current depressive episode.

As used in the context of the present invention, "suicidal ideation" refers to thinking about, considering, or planning suicide. A doctor or psychologist will diagnose a patient for the presence of suicidal ideation using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they suffer from suicidal ideation. In some cases, a patient experiencing suicidal ideation will be at risk for imminent suicide, or will be considered to have "suicidal intent."

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

"Clinical response" includes, but is not limited to, improvement on a rating scale.

The severity of the disorder, 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 efficacy of treatment.

The CGI rating scale was developed to provide a concise, independent assessment of the clinician's perception of a patient's global 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 CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is the patient currently?” Rated on a seven-point scale: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat severely ill; 6 = severely ill; and 7 = the sickest patient.

The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, there is only one inquiry rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

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

The severity of the disorder, as well as changes in severity, can be further assessed using rating scales appropriate for the specific psychiatric or neurological disorder that the patient suffers from.

Individual items as well as subcombinations of individual items of the scales as described herein can be used to assess specific disease aspects.

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

When clinical response is assessed at an early time point (e.g., 2 hours) after drug administration based on endpoints developed for longer recall periods (e.g., typically 7 days for MADRS), reasonable modifications to such endpoints can be made (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration).

The considerations outlined apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

At later time points, such as on day 1 or later, all items of the relevant scales used to assess clinical response can usually be assessed using an appropriate recall period (if necessary) so that no pre-treatment scores need to be carried forward. For example, if the BIMF is assessed on day 7, a recall period of seven days would be used (rather than the standard recall period of 2 weeks).

As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. Preferably, the active compound is administered by inhalation, nasal, buccal or sublingual administration.

As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined order of one or more separate administrations.

As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and tiny suspended solid and/or liquid particles. The term "degradation product" refers to a compound produced by chemical modification of an active agent due to a chemical reaction during the formation of the aerosol. Such reactions include, but are not limited to, oxidation. When describing the percentage of "degradation product" in the context of the present invention, this refers to the number of active agent degradation products present in the sample divided by the number of active agents present in the sample plus the number of active agent degradation products multiplied by 100%, that is, (the sum of the number of all active agent degradation products present in the sample)/((the number of active agents present in the sample)+(the sum of the number of all active agent degradation products present in the sample)) x 100%. As used herein, the term "impurity" refers to an unwanted compound that contaminates an active agent sample. Impurities may have been contained in the starting material before the aerosol is formed, or may be degradation products.

The term "purity" refers to 100% minus the percentage of all active agent degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) / (the amount of active agent present + the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) x 100%.

The term "mass median aerodynamic diameter" (MMAD) is the diameter such that 50% of the particles present in the aerosol are larger than this calculated diameter and 50% are smaller than this calculated diameter. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the mass of aerosolized active agent per unit aerosolization time.

Mental and nervous system disorders

Psychiatric and neurological disorders to be treated according to the present invention have in common that they are associated with one or more of the symptom clusters discussed below, including sleep disturbance, 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 breastfeeding mother patient diagnosed with a psychiatric or neurological disorder.

The mental or nervous system disorder is suitable for treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The mental or nervous system disorder is particularly major depressive disorder, persistent depressive disorder, bipolar disorder, anxiety disorder, post-traumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder or psychoactive substance abuse.

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

In another preferred embodiment, the psychiatric disorder is bipolar disorder, such as bipolar disorder type II. Patients diagnosed with bipolar disorder will particularly suffer from a current major depressive episode.

Various aspects of bipolar disorder, such as sleep disturbances, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social/emotional withdrawal or alienation (anhedonia, emotional withdrawal, and emotional apathy) can be improved. Other aspects of the disease that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation). The improvements achieved are reflected on clinically relevant scales.

Scales for the assessment of mental and neurological disorders

A variety of scales have been proposed to assess the severity of psychiatric or neurological disorders.Such scales are based on tests that can be self-administered or administered by a clinician.

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

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

The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2 to 3 hours after the last administration. Early assessment can generally be performed, for example, about 2 hours or about 3 hours after the last administration.

However, assessment of sleep disrupting effects or effects on psychiatric or neurological disorders associated with sleep disrupting effects can be performed as early as the day after treatment (ie, day 1), allowing the treated patient an opportunity to get at least one night of sleep.

Thus, an assessment on day 1 or day 1 means an assessment on the second day after administration. The assessment will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. The assessment may be performed after about 24 hours.

Assessment on or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

For example, when one of the scales is used to assess the severity of a mental or nervous system disorder, when evaluating clinical response at an early time point (e.g., 2 hours) after drug administration based on an endpoint developed for a longer recall period (e.g., MADRS is typically 7 days), such endpoints can be reasonably modified (e.g., changing the MADRS recall period to 2 hours and carrying forward the sleep items recorded at baseline before drug administration). Unless a recall period is specifically specified, the same applies to any other scale used herein to assess the therapeutic effect of a mental or nervous system disorder.

The considerations outlined apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

At a later time point, such as on day 1 or later, all items of the relevant scales used to assess clinical response can generally be assessed with an appropriate recall period (if necessary) so that no pre-treatment scores need to be carried forward.

Active Agent

Mental or neurological disorders have several features that result in a significant disease burden and should be treated appropriately. Therefore, treatments, especially pharmacological interventions, are needed not only to improve the overall disease score but also to improve specific aspects of the disease.

The inventors contemplate that carefully selected hallucinogens may result in improved treatment and may also result in overall improvements in the disorder and maternal functioning.

The inventors also contemplate that if treating a breastfeeding mother with a psychiatric or neurological disorder, carefully selected hallucinogens may allow breastfeeding to continue without near-total interruption.

A group of hallucinogens consists of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often called "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, of which the indoleamines are divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-associated receptors.

Recently published studies using serotonergic psychedelics such as LSD, psilocybin, and DMT (using the shamanic medicine ayahuasca containing DMT) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may hamper 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) reported a patient who had a manic episode after taking LSD or an LSD analog. The patient had symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 3 weeks later. 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) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, A.G., Valerio, M.P. and Jose MSmith, 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) reported a man with bipolar disorder who switched to mania after drinking ayahuasca, a beverage containing DMT.

Another case report 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 inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for use in therapy. 5-MeO-DMT has unique pharmacological properties that are distinct from other psychedelic compounds.

5-MeO-DMT is a potent, fast-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 than other classic psychedelics.

As further detailed in the Examples section below, the inhibition constants (Ki values) of psilocin (the dephosphorylated form of psilocybin formed after ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while psilocin and DMT exhibit moderate affinity. The inhibition constants ( _{Ki values} ) of psilocin, DMT, and 5-MeO-DMT at the 5-HT2A receptor located in the frontal cortex of postmortem human brains are 37, 117, and 122 nM, respectively. Thus, psilocin exhibits moderate/strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

Compared to other psychedelics (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing a significant risk of inducing mania or hypomania in patients suffering from psychiatric 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 disorder type I and bipolar disorder type II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT/ayahuasca, psilocybin, LSD).

The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

Further, it has been reported that antidepressants induce isolated hypomanic episodes in patients suffering from 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 showed no evidence of inducing hypomania.

5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective, described as a "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after inhalation, compared to hours with, e.g., oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

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

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 role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

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

The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep/wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social/emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

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

5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

The inventors studied 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 dosing.

Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

The inventors have further determined that 5-MeO-DMT has multiple characteristics that make it an attractive treatment for PPD. Compared to SSRIs, 5-MeO-DMT is a rapid-acting agent (in the 5-MeO-DMT-TRD trial, 5 of 8 TRD patients achieved remission within 2 hours of dosing, 8 patients achieved remission on day 1, and 7 patients maintained remission on day 7). Treatment of patients with PPD with 5-MeO-DMT can rapidly improve not only depressive symptoms, but also maternal functioning. In addition, 5-MeO-DMT is administered during a single day of treatment, optionally with infrequent re-dosing, thus distinguishing it from SSRIs, which require a long-term daily dosing regimen with low compliance, and brexanolone, which requires long-term infusions and hospitalization.

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

Furthermore, the inventors have determined that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows for continued breastfeeding with only brief interruptions to treatment.

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

These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

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

Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

Methods for the preparation of these compounds are known in the art.

Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar 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. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

Examples of suitable organic moieties are C(O) ^OR1 , -C(O) ^R2 , -CH( ^R3 ) ^OR4 , -C(O)OCH( ^R3 )OC(O) ^R4 , -C(O)OCH( ^R3 )OC(O) ^OR4 , -CH( ^R3 )C(O) ^R4 , -CH( ^R3 )OC(O) ^R4 , -CH( ^R3 )OC(O) ^OR4 , wherein each of ^R1 , ^R2 , ^R3 and ^R4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

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

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

Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

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

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

Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

Mode of administration

The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, by nasal administration, by buccal administration, or by sublingual administration. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art. For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably the hydrobromide salt) or in the form of a formulation of a pharmaceutically acceptable salt (preferably the hydrobromide salt). Examples of suitable devices are known in the art.

Buccal or sublingual administration may also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, preferably the hydrobromide salt, itself or in the form of a formulation, such as a tablet, film, spray, cream, as is known in the art.

Administration is particularly carried out by inhalation of an aerosol. This aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l. The pharmaceutically acceptable gas is preferably air.

The aerosol particles preferably contain less than 1% by weight of impurities, in particular less than 0.5% by weight of impurities. In addition, they preferably contain less than 0.5% by weight of 5-MeO-DMT degradation products, in particular less than 0.2% by weight of 5-MeO-DMT degradation products, which are produced by chemical modifications of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

In a further preferred aspect, the aerosol consists essentially of: (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The aerosol particles preferably contain 5-MeO-DMT in the free base form.

The aerosol is preferably characterised by having a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular less than 2 μm and greater than 0.1 μm.

The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT to generate aerosol particles. The thin layer can have a thickness of less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

A thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via air passing through the thin layer. Alternatively, a thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via the solid support.

The air passing through the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the thin layer may in particular have a temperature of about 210° C. and pass through the thin layer at a rate of about 12 l/min for about 15 seconds.

The aerosol particles may be contained in a volume equal to or less than about 3 liters, in particular contained in a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. Delivery to the patient is preferably via a single inhalation.

5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. These aerosols have a suitable aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

Aerosols that can be used in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is difficult to predict which conditions are suitable for safe, efficient and predictable aerosolization, particularly when the aerosol is to be used for systemic delivery of the compound to a patient via the lungs. The relevant variables in this context include a) the dosage of the compound, b) the morphological state (e.g., crystalline form or thin layer form) of the compound that can be used for aerosolization, c) the amount of thermal energy to which the compound is exposed (defined by temperature and exposure duration) and d) the volume (defined by flow rate and airflow duration) of the air introduced to form the aerosol.

The compositions and methods described herein are used to safely, efficiently, and predictably deliver 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient systemically by inhalation. "Safe" means that the aerosol particles should contain only minimal amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized to a specified extent, preferably almost completely aerosolized or completely aerosolized, i.e., the aerosol has the desired physical properties so that the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is delivered systemically via the lungs primarily via absorption in the alveoli, and the patient can inhale the aerosol in a single inhalation (i.e., within one deep breath), and "predictable" means that there is little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

A suitable aerosol can be achieved by a) providing a therapeutically effective amount of 5-MeO-DMT in the form of a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to an elevated controlled temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a thin layer of 5-MeO-DMT disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% by weight impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

An aerosol volume deliverable to a patient via a single inhalation that is characterized by a mass median aerodynamic diameter of less than 3 microns, less than 1 weight percent impurities, and less than 0.5 weight percent 5-MeO-DMT drug degradation products can be generated by defining the following: a) the dose of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the temperature and the duration of exposure), and d) the total amount of air that passes through the thin layer of 5-MeO-DMT (defined by the airflow rate and the duration of airflow).

Preferably, the 5-MeO-DMT thin layer is exposed to thermal energy via air passing through the thin layer, in which case the air is heated. The heated air passing through the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the thin layer may particularly have a temperature of about 210° C.

Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy via a solid support, in which case the air passing through the thin layer is not heated, but the solid support is heated. The heated solid support may have a temperature in the range of about 180°C to about 420°C.

Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, at least 99%, preferably at least 99.5%.

Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT disposed on the solid support is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders having a diameter less than 1.0 mm, boxes having a thickness less than 1.0 mm, and nearly any shape filled with small holes (e.g., less than 1.0 mm in size). Preferably, the solid support provides a large surface area to volume ratio (e.g., greater than 100/meter) and a large surface area to mass ratio (e.g., greater than 1 ^cm2 /gram).

A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet with a thickness of 0.25 mm has a surface area to volume ratio of about 8,000/meter. Rolling the sheet into a hollow cylinder with a diameter of 1 cm produces a support that retains the high surface area to mass ratio of the original sheet, but has a lower surface area to volume ratio (about 400/meter).

A variety of different materials are used to construct the solid support. Classes of such materials include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of material classes: aluminum, silver, gold, stainless steel, copper, and tungsten; silicon dioxide, glass, silicon, and aluminum oxide; graphite, porous carbon, carbon yarn, and carbon felt; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coating variations of materials may also be used.

When aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina with a defined surface area greater than 2 ^m2 /g from Aldrich, St. Louis, Mo.), and silicon wafers used in the semiconductor industry. Carbon yarn and carbon felt can be obtained from American Kynol, Inc., New York, NY.

Preferably, the thickness of the 5-MeO-DMT layer disposed on the solid support is less than about 10 μm, in particular less than about 7.5 μm. The layer may have a thickness in the range of about 0.1 μm to about 10 μm, in particular in the range of 0.3 μm to 7.5 μm.

Preferably, the total amount of air passing through the 5-MeO-DMT thin layer is limited to about 6 liters/minute to about 40 liters/minute, preferably about 8 liters/minute to about 16 liters/minute of flow velocity, and the duration of the air flow is selected so that the cumulative volume of the aerosol is no more than about 3 liters, preferably about 1 liter to 3 liters, such as 2 liters to 3 liters.For example, when the air flow rate is about 6 liters/minute, the air flow duration should be less than about 30 seconds.A useful specific air flow rate and duration are about 12 liters/minute and about 15 seconds, thereby produce about 3 liters of aerosol volume.Another useful specific air flow rate and duration are 10 liters/minute and about 15 seconds, thereby produce about 2.5 liters of aerosol volume.Another useful specific air flow rate and duration are 8 liters/minute and about 15 seconds, thereby produce about 2 liters of aerosol volume.Another useful specific air flow rate and duration are 10 liters/minute and about 12 seconds, thereby produce about 2 liters of aerosol volume.

The aerosol formation rate is greater than 0.1 mg/second.

The aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as about 0.5 mg/l to about 12.5 mg/l, preferably about 1.3 mg/l to about 10 mg/l, in particular about 2 mg/l to about 9 mg/l.

The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, most preferably less than 2 microns and greater than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% by weight impurities, preferably less than 0.5% by weight impurities.

The 5-MeO-DMT aerosol particles are characterized by less than 0.5 wt % 5-MeO-DMT degradation products, preferably less than 0.2 wt % 5-MeO-DMT degradation products.

A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a 12 mg dose of 5-MeO-DMT configured as a thin layer less than 5 microns thick on a solid support to a temperature of 210° C. for 15 seconds by passing heated air through the thin layer; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% impurities and less than 0.5% by weight of 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

Those skilled in the art who understand the aerosol characteristics and aerosolization conditions defined in the present invention can determine suitable gasification devices or systems, which result in desired aerosol characteristics. Examples of such suitable gasification devices or systems include, for example, Volcano Medic gasification systems (Storz & Bickel, Germany) with associated dosing capsules with a drip pad; disclosed in, for example, EP 0 933 093 B1 and EP 1 884 254 B1 and registered community design 003387299-0001) and Staccato devices (Alexza Pharmaceuticals, Mountain View, USA; disclosed in, for example, US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The generated aerosol can be collected in the balloon and inhaled by the patient from the balloon.

Dosage regimen

The present invention also provides dosage ranges, specific dosages, and dosing regimens (administration regimens).

The present invention is based in part on the inventors' conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT, which drives the therapeutic benefits of 5-MeO-DMT in patients suffering from psychiatric or neurological disorders, particularly one or more aspects as defined above, either causally or at least as a surrogate behavioral marker of a potential unknown therapeutic mechanism.

Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility across individual patients would result in a better therapeutic profile than with previously tested psychedelics and dosing regimens.

Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be achieved with other psychedelics due to the late onset and prolonged duration of the psychedelic effects and due to the rapid development of tolerance (i.e., the psychedelic effects diminish or disappear upon re-administration), which may persist for several days.

Patients diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder and including the disorder associated with suicidal ideation, as defined herein, are treated by administering 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e., the patient is not receiving treatment for any other psychiatric or neurological disorder or its associated symptoms.

The dosage of 5-MeO-DMT administered to a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder and including such disorder associated with suicidal ideation) is in the range of about 1 mg to about 25 mg, or any amount within the range, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Please note that in this specification, when a range is listed (such as "about 1 mg to about 25 mg"), the inventors contemplate all discrete values within the range, some of which are explicitly mentioned, but not all of them - this is simply for the purpose of brevity.

In preferred embodiments, improved methods of treating a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder, and including such disorder associated with suicidal ideation) using a therapeutically effective amount of 5-MeO-DMT comprises a clinical response occurring no later than about 2 hours after administration of the 5-MeO-DMT.

In preferred embodiments, improved methods of treating patients diagnosed with a disorder as defined herein, including treatment-resistant forms of such disorder, and including such disorder associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

In preferred embodiments, improved methods of treating a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder, and including 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, the more than 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, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

In an embodiment, the dose 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 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until 20 mg is reached, or all administrations within that treatment block have been administered, whichever is earlier.

In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: 20 mg is reached, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

For embodiments where the dose of a subsequent administration is increased, the dose of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg to the dose of the previous administration. For example, if the first administered dose is 6 mg and the dose increase is 6 mg, the second administered dose is 12 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administered dose is 18 mg.

In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg at the first administration, and then increased to a dose selected from about 8 mg to about 14 mg at the second administration, and to a dose selected from about 14 mg to about 20 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 2 mg to about 8 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 20 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 18 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 18 mg.

In a most preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 2 mg to about 8 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 8 mg to about 14 mg, and the third administration in the first treatment block will be increased to a dose selected from about 14 mg to about 20 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

It will be appreciated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens and that the appropriate weight of the salt to be administered may be calculated based on the specified weight of the free base, assuming equimolar amounts are used.

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

Patients can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

Patients experiencing a “peak psychedelic experience” can also be identified by achieving at least 60% of the highest possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 to the following three questions: 1. How intense was the experience; 2. How much loss of control was there; 3. How significant (i.e., profound and important) was the experience?

Sleep disturbances

There are two basic types of sleep: 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 depth of sleep. Non-REM and REM sleep alternate during the four to five cycles of normal human sleep each night. During the early part of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, especially in the first sleep cycle. As the night progresses, non-REM sleep becomes lighter, and more of each cycle is allocated to REM sleep.

Normal, healthy sleep consists of the different stages described above, which proceed in a continuous, strictly controlled sequence throughout the night.

Disruptions in this tight control can lead to sleep disturbances.

Sleep disturbances are conditions that affect the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition (such as a psychiatric or neurological disorder). Sleep disturbances can affect a person's ability to function normally while awake.

Common forms of sleep disturbances include disorders of falling asleep and maintaining sleep (insomnias), disorders of excessive sleepiness (hypersomnias), disorders of the sleep-wake schedule (circadian rhythm disorders), disorders related to sleep, sleep stages, or partial arousals (parasomnias), disorders characterized by disturbed 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 the patient has difficulty falling asleep or staying asleep. People with insomnia have trouble falling asleep; wake up frequently during the night and have difficulty falling asleep again; wake up too early in the morning; have poor sleep quality; and/or have at least one daytime problem due to poor sleep quality, such as fatigue, sleepiness, mood problems, difficulty concentrating, accidents at work or while driving, etc.

Hypersomnia is characterized by excessive daytime sleepiness and/or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in patients with hypersomnia. Transitioning from sleep to wakefulness is difficult. Individuals who experience sleep drunkenness report being confused, disoriented, slowed down, and falling asleep again and again upon waking.

Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances due to alterations in an individual's internal circadian rhythm or due to inconsistencies between their circadian rhythm and their desired or required work or social schedules. This desynchronization may be temporary or persistent. The ensuing clinical presentation combines symptoms of insomnia and hypersomnia. Sleep duration is often shortened and interrupted, performance in the desired wakefulness state is impaired, and restoration of a normal sleep schedule is temporarily impossible.

Parasomnias refer to various forms of sleep disorders characterized by people experiencing unusual behaviors or physiological activities (such as sleepwalking or nightmares) before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias may 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 the respiratory muscles and the control center in the brain. One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals to control breathing, for example, depending on an underlying health condition. Central sleep apnea has potentially serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow leads to intermittent hypoxia, which causes sleep fragmentation due to micro-arousals or awakenings. The consequence can be excessive daytime sleepiness.

In sleep-related movement disorders, repetitive, relatively simple, often stereotyped movements disrupt sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

Insufficient sleep duration or quality may lead to personality changes and may not only exacerbate existing mental illnesses, but may also be a contributing factor to their development. Sleep disturbances may also interfere with cognitive function and lead to impairment of memory. Sleep-deprived subjects may experience difficulty in decision-making, irritability, poor performance, and may have slower reaction times. Insufficient sleep can also adversely affect 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 unsuccessful, treatment may involve medication or psychotherapy.

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

In patients suffering from sleep disturbances associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorders do not necessarily improve the sleep disturbances.

For example, sleep disturbances are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of the accompanying sleep disturbances. Although most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while other antidepressants may cause sleep impairment.

Although disrupted sleep may be considered a condition that should be treated independently of any other condition, disorder, or symptom an individual may have, several psychiatric and neurological disorders are associated with disrupted sleep. Of note, the relationship between sleep and psychiatric or neurological disorders is often bidirectional. Not only can psychiatric or neurological disorders negatively impact healthy sleep patterns, but disrupted sleep can also be a contributing factor to the onset, progression, and prognosis of mental health or neurological disorders.

Treatment according to the invention may reduce or eliminate sleep disturbances and preferably may also improve associated psychiatric or neurological disorders.

Measuring sleep disturbances

Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of wakefulness throughout the night. Quantitative indicators can be measured using objective methods, including polysomnography, actigraphy, and determination of sleep latency, or by self-report measurements (questionnaires).

Polysomnography is a technique that requires patients to be monitored throughout the night in a specialist clinic. Various functions are measured throughout the night, including eye movements, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body posture and movement, snoring and heart rate.

Another quantitative measurement is actigraphy. Actigraphy sensors are worn to measure motor activity, which is continuously recorded and used to assess sleep-wake cycles. This technology allows patients to continue their normal lives while recording the required data in a natural sleep environment.

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

The sleep rating questionnaire captures ratings of components of sleep quality, such as perception of sleep depth, difficulty in waking, and rest after sleep, as well as other factors that may affect sleep quality, such as comorbidities and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep discomfort may often persist despite normal values for quantitative sleep measures.

Questionnaires not only facilitate rapid and accurate assessment of complex clinical problems but may also be useful in tracking the patient's progress.

A variety of sleep quality indices are known. The following indices include examples of questionnaires for assessing general sleep and examples of questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders and parasomnias, respectively. However, the present invention is not limited to the use of a particular index or questionnaire.

Some questionnaires rely on a recall period (recall window) of several days or even weeks. While this may be suitable for diagnosing sleep disorders, it is not always suitable for assessing the effectiveness of treatments, especially those that start quickly after treatment. For several questionnaires, the recall period can be modified so that the scores obtained reflect a period of time after treatment. In particular, this article discusses questionnaires for assessing the effects of treatment on sleep in patients suffering from specific conditions, which rely on a recall period that starts no earlier than the time point when the acute psychedelic experience subsides after the last administration. In order to meet this criterion, the normally applied recall period is modified if necessary.

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

The Sleep-50 questionnaire consists of 50 items, which are designed to screen various sleep disorders in the general population. The scale consists of nine subscales, reflecting some of the most common disorders and discomforts associated with sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs/periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily function. For each item, the respondent will get a scale from 1 ("not at all") to 4 ("very much"), and is asked to indicate the degree of match between the statement and their experience in the last month or another appropriate recall window.

To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the respondent must also achieve a cutoff point of at least 3 or 4 ("quite a lot" or "very much", respectively) on a subscale assessing the impact of sleep discomfort 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 decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

A commonly used questionnaire to assess sleep disturbance is the Pittsburgh Sleep Quality Index. Other tools are the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System (PRIME). )Sleep disorders.

The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-rating questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. The 19 items are divided 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 scored from 0 to 3. Higher scores indicate more severe sleep disturbance. A detailed scoring description of the Pittsburgh Sleep Quality Index can be found in the appendix of 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 create an overall score ranging from 0-21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas, or moderate difficulty in more than three areas.

If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

The Insomnia Severity Index (ISI) is a short questionnaire that relates to subjective sleep quality, severity of symptoms, subjective satisfaction with sleep, degree of interference of insomnia with daily functioning, how significant the respondent feels their insomnia is compared to other people, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (=none) to 4 (=very); higher total scores correspond to more severe insomnia. Total scores of 0-7 represent "no clinically significant insomnia", 8-14 mean "subthreshold insomnia", 15-21 are "clinical insomnia (moderate severity)", and 22-28 mean "clinical insomnia (severe)" (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. Another appropriate recall window may also be used.

Treatment success is indicated by (i) a decrease in the score, for example a decrease of >7 points, particularly >8 points; preferably (ii) a decrease in the score to below the cut-off value for clinically significant insomnia.

The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ rates restlessness/agitation, mental overactivity, consequences of insomnia, and lack of sleep preparation, with a particular focus on beliefs about the root causes of sleep problems. Respondents use a five-point scale to indicate how often certain statements about insomnia represent their experiences. 1 means "never true," and 5 means "often true." The higher the score, the more abnormal the belief in the causes and associated factors of insomnia (A. Shahid et al., supra).

A decrease in the score indicates successful treatment.

Patient Reported Outcomes Information System The Sleep Disturbance Tool is a general method for assessing sleep disturbances. The tool has one long form and four different short forms (e.g., 4, 6, and 8 items) and assesses self-reported sleep quality, perception of sleep depth, and any perceived difficulties related to falling asleep and staying asleep over a 7-day period.

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

A decrease in T score indicates successful treatment.

Excessive sleeping 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) evaluates overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, which represent moments of relative inactivity, such as an afternoon nap or sitting in a car stopped in traffic. Respondents rate their likelihood of falling asleep using a scale of 0-3 (0 means "never doze off," and 3 means "very likely doze off"). The scoring range is 0-24; the higher the score, the higher the severity of daytime sleepiness. A cutoff score of 10 indicates that daytime sleepiness may occur at a clinical level (A. Shahid et al., supra).

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

The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses the degree of sleepiness at a particular moment. The scale consists of only one item, asking the respondent to select one of seven statements that best represents their current perceived sleepiness level. The sleepiness level is assessed using a scale from 1 (=feeling active and energetic; alert; fully awake) to 7 (=almost in a trance; falling asleep quickly; unable to stay awake) (A. Shahid et al., supra).

A decrease in the score indicates successful treatment.

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

The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnias, assesses their frequency, and includes an evaluation 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 the score, preferably (ii) a decrease in the score below a cut-off value.

A commonly used questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period may also be selected.

A decrease in the score indicates successful treatment.

The commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The questionnaire of the 10 items requires the respondents to use the Likert-type rating method to indicate how serious the impact of this disorder on them has been in the past week. The problem can be divided into one of two categories: disorder symptoms (nature, intensity and frequency) and their impact (sleep problems, daily functional disorders and resulting mood changes). Each of the ten questions requires the respondents to rate their RLS experience with a scale of 0 to 4, wherein 4 represents the most serious and most frequent symptoms, and 0 represents the least symptoms. The total score range can be 0 to 40. As a concise scale with excellent psychometric quality, the tool can be applied to a variety of research and clinical purposes, including screening and evaluating treatment outcomes. (A. Shahid et al., supra).

The response to treatment can be assessed by a decrease in the score.

Resting-state networking and sleep disturbances

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by 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 networks of connectivity have been found to be impaired in various disease states.Such disease states are associated with altered functional connectivity within a specific resting-state network and/or between one or more regions in one or more additional resting-state networks.

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

A key network involved in sleep is the default mode network (DMN). In general, the DMN is deactivated during tasks and activated during rest. It is involved in a variety of cognitive processes, such as higher-order 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 to sleep disorders.

As discussed further in this article, impaired resting-state networks can also be found in psychiatric or neurological disorders.

Resting-state networks associated with sleep disturbances can also be affected by psychiatric or neurological disorders caused by certain medical health conditions.

In patients with insomnia, functional connectivity impairments were observed within the default mode network (DMN) and within the salience network, which are associated with the detection and integration of emotional and sensory stimuli. Studies have shown that these networks contain key areas for the integration of emotional and physical states, and that functional connectivity impairments within and/or between these networks and other brain regions can account for patients' alertness, subjective distress, and poor sleep continuity.

The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, different DMN hubs (precuneus and medial prefrontal cortex) show significant changes, and functional connectivity in the DMN is associated with self-reported severity of sleepiness.

A study investigating differences between night-shift nurses and day-shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, involved in sleep regulation and cognitive functions such as responsiveness and alertness. In addition, functional connectivity of the DMN is fundamentally different in early and late circadian rhythm phenotypes. As with other forms of sleep disturbance, circadian rhythm disturbances can lead to changes in brain functional connectivity. Changes in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disturbances.

Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders representative of non-REM parasomnias.

The precuneus is involved in the analysis and integration of visual, auditory and somatosensory information and the monitoring of movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnias, the default mode network is affected.

Resting-state fMRI studies of patients with sleep-related breathing disorders, such as central sleep apnea, have demonstrated profound global and regional connectivity deficits, particularly in the default mode network (DMN) and in regions involved in arousal and sensorimotor systems.

Sleep-related movement disorders, such as periodic limb movements during sleep, were reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. In addition, activity in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem, could be observed.

In many cases, abnormal functional connectivity of resting state networks associated with sleep disturbances are also associated with the above-mentioned disorders. Therefore, according to the present invention, influencing these networks by the therapy according to the present invention will lead to an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric disorder or a neurological disorder, also to an improvement in said disorder.

Treatment of sleep disorders and psychiatric and neurological disorders

According to the present invention, idiopathic sleep disorders and sleep disorders in patients suffering from mental disorders or nervous system disorders can be treated. In patients suffering from sleep disorders associated with mental disorders or nervous system disorders, the treatment of sleep disorders according to the present invention leads to the improvement of the diseases associated with sleep disorders.

In many cases, resting-state networks associated with sleep disturbances are also implicated in the above disorders.

5-MeO-DMT is able to interrupt established functional connectivity patterns of resting-state networks. This disruption results in a reset of pathological, poorly connected brain connections as the network rewires. New, healthy functional connections are established, and this has a lasting effect.

The neuroplasticity-promoting properties of 5-MeO-DMT may explain the persistence of this effect. 5-MeO-DMT specifically promotes structural and functional plasticity at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT modulates the morphogenesis and maturation of dendritic spines, thereby initiating the formation of new synaptic connections. These new connections will be strengthened, weakened, or even eliminated depending on activity.

The resulting new synapses in turn affect the activity patterns of neurons. The inventors conclude that such reciprocal structural and functional modifications contribute to the proper establishment of networks and the persistence of effects following administration of 5-MeO-DMT.

From a biochemical point of view, 5-MeO-DMT interacts with, among other things, the 5-HT receptor.

5-HT receptors, receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A variety of physiological and pathological functions are mediated by 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 different spatial distributions.

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

In addition to the 5-HT1A and 5-HT2A 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 role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

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

The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep/wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social/emotional withdrawal. This is supported by the clinical results shown in the studies mentioned herein.

Treatment according to the invention will result in an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric or neurological disorder, will also result in an improvement in said disorder.

Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) demonstrate that sleep disturbances can be successfully treated by administering 5-MeO-DMT.

In the TRD study described in more detail in the Examples section below, the MADRS item "Sleep reduction" reflecting insomnia was assessed, among others.

The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the normal pattern of the subject's own health. When the subject's sleep is normal, the score is 0. A score of 2 reflects mild difficulty falling asleep, or slightly reduced, shallow or intermittent sleep time. A score of 4 means that sleep time is reduced or interrupted by at least two hours. A score of 6 means less than two or three hours of sleep.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

Thus, the score of the scale item "sleep loss" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance, especially in patients suffering from psychiatric disorders or nervous system disorders.

Cognitive dysfunction

Cognition includes the skills needed for thinking, memory, attention, and problem solving. Loss or decline in these skills can lead to cognitive impairment, a term used in this article to refer to deficits or impairments in any cognitive domain. Cognitive impairment may be a manifestation of an underlying medical condition.

The DSM-5 defines six key areas of cognitive function: complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition.

Cognitive dysfunction can affect one or more of these areas. In fact, cognitive abilities are highly correlated, and it is not uncommon for more than one area to be affected.

For example, the domain complex attention has the subdomains sustained attention (often called “concentration” or “focus”), divided attention, selective attention, and processing speed.

Therefore, complex attention clearly encompasses aspects that are critical to a variety of cognitive tasks, such as executive function as well as learning and memory. Cognitive control or executive function is essentially attention. In addition, perception and decision-making are also deeply influenced by attentional capacity.

Therefore, attention can be tested not only in isolation but also with cognitive control tasks/executive functions. If attention is impaired, other types of cognitive abilities may also be impaired. One must pay attention to stimuli before one can comprehend language, perceive visual-spatial relationships, remember information, or solve problems.

Cognitive dysfunction (the term being used herein to refer to an acquired disorder and thus representing a decline from a previously achieved level of function) can be related to a variety of processes.

In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained during aging and may even improve over time. However, even in the absence of any pathological disorder, aging can lead to a decline in abilities such as abstract thinking, reasoning, and decision-making. These deteriorations are associated with potential age-related deficits in processing speed, attention, memory, and executive function that indicate cognitive aging.

In addition to normal aging, cognitive impairment may be associated with a psychiatric or neurological disorder or some other medical condition.

Mental or neurological disorders such as those discussed herein may result in or be associated with cognitive dysfunction.

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

Cognitive dysfunction can take the form of neurocognitive disorders.

Mild neurocognitive disorder, also known as mild cognitive impairment, is characterized by a small decline in cognitive ability from previous performance levels in one or more cognitive domains. Affected patients are still able to maintain independence and complete daily tasks. However, patients' functioning is usually at a suboptimal level. Daily tasks become more strenuous as compensatory strategies are used to maintain independence.

In severe neurocognitive impairment, a significant decline in cognitive ability from previous performance levels is observed in one or more cognitive domains. Cognitive deficits interfere with independence in daily activities.

Measuring cognitive impairment

Cognitive impairment can be assessed using questionnaires or neuropsychological assessments.

Questionnaires assess a person's mental status based on observations by the person, a caregiver, or a clinician who fills out the questionnaire. Questionnaires used to assess a person for specific mental or neurological disorders may include items related to cognitive function.

A neuropsychological assessment is a process that comprehensively evaluates a person's cognitive, psychological/emotional, and behavioral functioning. A core component of a neuropsychological assessment is the administration of neuropsychological tests to formally assess cognitive functioning.

Performance on these tests is compared to standards appropriate for the patient's age, education, and cultural background. Testing usually uses a performance-based set of questions, also called a neuropsychological battery.

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

Common tests used to assess cognitive impairment are the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog ^™ , the Screening for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses different cognitive domains: short-term memory; visuospatial abilities; executive functions; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30, with 26 or more being normal, 18-25 being mild cognitive impairment, 10-17 being moderate cognitive impairment, and less than 10 being severe cognitive impairment.

The Mini-Mental State Examination (MMSE) is an 11-question measurement tool that tests five areas of cognitive function: orientation, recording, attention and calculation, recall, and language. The maximum score is 30. The original score may also need to be modified based on education and age.

Four cut-off levels were used to classify the severity of cognitive impairment: 24-30 means no cognitive impairment; 19-23 means mild cognitive impairment; 10-18 means moderate cognitive impairment; and ≤9 means severe cognitive impairment.

Used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

The Mini-Cog ^TM is a brief screening questionnaire for cognitive impairment. It combines a 3-word recall with a clock drawing test. The clock drawing test assesses a number of cognitive domains that may be affected, such as executive function, visuospatial abilities, motor programming, and attention. After taking the clock drawing test, one point is awarded for each three words correctly recalled; a correct drawing of a clock is worth two points. A score < 4 indicates cognitive impairment.

The Screening for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening tool that examines cognitive performance in patients with psychiatric disorders.

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). There are three different test formats to facilitate repeated testing, which can reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score below 70 indicates cognitive impairment.

Cognitive dysfunction may also be assessed using the MCCB (MATRICS Consensus Cognitive Battery) or one or more of its different subtests. These subtests include: Trail Making Test Part A (tests processing speed); Brief Assessment of Cognitive Abilities in Schizophrenia, Symbol Coding Subtest (processing speed); Hopkins Verbal Learning Test-Revised, Immediate Recall, Three Learning Trials Only (verbal learning); Wechsler Memory Scale-3rd Edition, Spatial Span Subtest (working memory (nonverbal)); Letter-Digit Span Test (working memory (verbal)); Neuropsychological Assessment Battery, Maze Subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category Fluency Test, Animal Naming (processing speed); Mayer-Salovey-Caruso Emotional Quotient Test, Managing Emotions Branch (social cognition); and Sustained Performance Test, Same Paired Version (attention/vigilance).

The test battery is suitable for measuring cognitive changes.

Further testing included 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).

Potential mechanisms of cognitive impairment

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by 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 networks of connectivity have been found to be impaired in various disease states. Such disease states, including certain forms of cognitive dysfunction, are associated with altered functional connectivity within a specific resting-state network and/or between one or more regions in one or more additional resting-state networks.

Resting-state fMRI is particularly advantageous when studying groups affected by cognitive dysfunction because it enables the examination of functional connectivity while removing task demands that may be confounded by underlying cognitive or motor impairments.

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

Specifically, certain core networks, also called “higher-order cognitive networks,” appear to be critical for most mental activities.

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

Another core network is the default mode network (DMN). The DMN contains regions in the brain that are most active when an individual's attention is not focused on any specific task. Activity in the DMN is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, integration of cognitive and emotional processing, and free thoughts unrelated to the task.

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

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

The above networks do not operate independently. In fact, there are countless connections between them. Cooperation between networks is essential for the functioning of specific tasks.

Brain networks undergo functional reorganization throughout the lifespan, with concurrent effects on cognition. During healthy aging, age-related alterations are observed in higher-order cognitive networks.

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

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

Resting-state networks involved in cognition can also be affected by psychiatric or neurological disorders, as a consequence of certain medical health conditions, as well as unspecified neurocognitive disorders.

Furthermore, resting-state networks involved in cognition are affected by sleep disturbances such as insomnia. In fact, cognitive dysfunction and sleep impairment are associated.

Patients with disturbed sleep have worse cognitive function, and patients with cognitive impairment often also have impaired sleep.

Treatment of cognitive impairment

According to the present invention, cognitive dysfunction occurring in patients suffering from mental disorders or neurological disorders or medical health disorders leading to related mental or neurological disorders can be treated. In addition, cognitive dysfunction occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

Cognitive dysfunction in unspecified neurocognitive disorders may also be treated.

In a patient suffering from cognitive dysfunction associated with another disorder as detailed above, treatment of cognitive dysfunction according to the invention results in an improvement of the disorder associated with cognitive dysfunction.

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

Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and/or between resting-state networks. This disruption results in the resetting of pathological, poorly connected connections as the networks rewire. New, healthy functional connections are established, and this has lasting effects.

Thus, according to the present invention, affecting these networks through therapies as described herein will result in improvements in cognitive dysfunction and, if the patient being treated suffers from a psychiatric or neurological disorder, will also result in improvements in that disorder; if the patient being treated suffers from a medical health disorder that causes the relevant psychiatric or neurological disorder, will also result in improvements in the relevant psychiatric or neurological disorder; if the patient being treated suffers from a sleep disorder (e.g., insomnia), will also result in improvements in the sleep disorder (e.g., insomnia); if the patient suffers from an unspecified neurocognitive disorder, will also result in improvements in one or more other symptoms of the disorder.

To further support the clinical utility of 5-MeO-DMT in patients suffering from cognitive dysfunction, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in cognitive dysfunction, which is also commonly observed in patients suffering from other disorders.

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

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. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as items related to cognitive dysfunction) were associated with other disorders, in which cognitive dysfunction was based on similarly altered functional connectivity within and/or between the default mode network, executive control network, salience network, and dorsal attention network.

Multiple patients in the recruited cohort showed significant improvements, and this result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

More specifically, one aspect that can be treated by administering 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT can be administered to a patient to reduce or eliminate cognitive dysfunction, particularly difficulty concentrating, in the patient.

The MADRS item that is particularly relevant to impaired concentration and memory is "difficulty concentrating." This item represents difficulty collecting one's thoughts, resulting in an inability to concentrate, and is scored on a scale of 0 to 6. If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty collecting one's thoughts, the score is 2. If there is difficulty concentrating and maintaining thoughts, resulting in reduced ability to read or have a conversation, the score is 4. If the patient cannot read or talk easily, the score is 6.

In the study group that received the individualized dosing regimen, all eight patients had a total score of 30 for the MADRS item “difficulty concentrating” at baseline.

After 2 hours, the score dropped to 11, which corresponds to 19 points or 63% improvement. On the first day after treatment, the score dropped to 1, which corresponds to 29 points or 97% improvement. On the seventh day after treatment, the score dropped to 9, which corresponds to 21 points or 70% improvement.

In the 12 mg group, the total score for the MADRS item “difficulty concentrating” was 16 at baseline for all four patients.

After 2 hours, the score dropped to 7, which corresponds to 9 points or 56% improvement. On the first day after treatment, the score dropped to 2, which corresponds to 14 points or 88% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 13 points or 81% improvement.

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

More specifically, according to the present invention, treatment of a patient with 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cognitive dysfunction, reduces or eliminates the cognitive dysfunction, wherein the cognitive dysfunction is a defect or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition. For example, if the cognitive dysfunction affects the cognitive domain complex attention, such as one or more subdomains of the cognitive domain complex attention (selected from sustained attention, divided attention, selective attention, and processing speed), in particular sustained attention, the cognitive dysfunction is reduced or eliminated.

In patients suffering from cognitive dysfunction associated with a psychiatric disorder or a nervous system disorder, treatment of cognitive dysfunction according to the present invention results in an improvement of the symptoms associated with the cognitive dysfunction.

Although cognitive dysfunction may be considered a condition that should be treated independently of any other conditions, disorders, or symptoms that an individual may have, several psychiatric and neurological disorders are associated with cognitive dysfunction. Of note, the relationship between cognitive dysfunction and psychiatric disorders is often bidirectional. Not only can psychiatric disorders negatively affect cognitive function, but cognitive dysfunction can also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

In many cases, resting-state networks implicated in cognitive dysfunction are also implicated in these disorders.

5-MeO-DMT is able to interrupt established functional connectivity patterns of resting-state networks. This disruption results in a reset of pathological, poorly connected brain connections as the network rewires. New, healthy functional connections are established, and this has a lasting effect.

anxiety

Anxiety is sometimes defined as "the apprehensive anticipation of future danger or misfortune, accompanied by feelings of dysphoria or physical symptoms of tension."

Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are only subjectively perceived as threatening, often accompanied by muscle tension, restlessness, fatigue, difficulty breathing, abdominal tightness, nausea, and difficulty 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/medication-induced anxiety disorders.

In addition, anxiety is associated with several other psychiatric and neurological disorders. Anxiety is also associated with sleep disturbances.

Measuring anxiety

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

The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. The scale is administered by a clinician. The scale has 14 items and can be divided into a mental group of items (items 1-6 and 14), which specifically measure mental agitation and psychological distress, and a physical group of items (items 7-13), which specifically measure physical discomfort associated with anxiety.

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

The interviewer rated each item on a scale of 0 to 4: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

A total score is obtained by summing the 14 items. The total score range is 0–56. Higher scores indicate more severe anxiety.

A score of ≤7 was considered to represent no anxiety or very low anxiety; a score of 8-14 represented mild anxiety; a score of 15-23 represented moderate anxiety; and a score of ≥24 represented severe anxiety.

The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, with a focus on physical symptoms. The items are rated on a four-point Likert scale, ranging from zero (not at all) to three (severe: I can hardly stand it). The total score ranges from 0 to 63.

The term "subthreshold anxiety" as used herein specifically means that the patient's Hamilton Anxiety Rating Scale (HAM-A) score is at least 9 but less than 18, and/or the Beck Anxiety Inventory (BAI) score is at least 11 but less than 16.

Potential mechanisms of anxiety

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by 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 networks of connectivity have been found to be impaired in various disease states. Such disease states, including some forms of anxiety, are associated with altered functional connectivity within specific resting-state networks and/or between one or more regions in one or more additional resting-state networks.

According to such studies, multiple brain regions have been implicated in anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal connectivity between amygdala-frontal and frontal-striatal regions. Anxiety and anxiety disorders are associated with specific alterations in resting-state networks.

Anxiety and anxiety disorders show abnormalities within and/or between the default mode network, the salience network, and the sensorimotor network. The resting state balance within and/or between each of these networks is different in different anxiety disorders.

Treatment of anxiety

According to the present invention, anxiety occurring in patients suffering from anxiety disorders or other psychiatric disorders or nervous system disorders associated with anxiety can be treated. In addition, anxiety occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

In patients suffering from anxiety associated with another psychiatric or neurological disorder or a sleep disturbance (eg insomnia), anxiety treatment according to the invention results in an improvement in the anxiety-related symptoms.

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

Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and/or between resting-state networks. This disruption results in the resetting of pathological, poorly connected connections as the networks rewire. New, healthy functional connections are established, and this has lasting effects.

Thus, according to the present invention, affecting these networks through therapies as described herein will result in improved anxiety, and if the patient being treated suffers from another psychiatric or neurological disorder related to anxiety, that disorder will also be improved; if the patient being treated suffers from a sleep disorder, such as insomnia, that sleep disorder (e.g., insomnia) will also be improved.

To further support the clinical utility of 5-MeO-DMT in patients suffering from anxiety, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in anxiety, which is also commonly observed in patients suffering from other disorders.

The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). Although TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for anxiety disorders and other anxiety-related disorders.

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. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items, such as those related to anxiety, were associated with other disorders where anxiety was based on similar altered functional connectivity within and/or between resting-state networks.

Multiple patients in the recruited cohort showed significant improvements, and this result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

More specifically, one aspect that can be treated by administering 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to a patient to reduce or eliminate anxiety in the patient.

A particularly relevant BPRS item in this context is "Anxiety." This item relates to reported worry, nervousness, fear, panic, or concern. Possible scores are:

1- No Anxiety

2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

3 - Mild. Frequent worrying but able to easily shift attention to other things.

4-Moderate. Worried most of the time and unable to easily redirect attention, but functioning is not impaired; or anxious occasionally with autonomic symptoms, but functioning is not impaired.

5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms or some areas of functioning are disrupted by anxiety or worry.

6 - Severe. Anxiety is daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

In the study group that received the individualized dosing regimen, the total score for the BPRS item “anxiety” was 37 at baseline for all eight patients.

After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points or 54%.

In the 12 mg group, the total score of the BPRS item “anxiety” was 25 at baseline for all 4 patients.

After 3 hours, the score dropped to 11, which corresponds to an improvement of 14 points or 56%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%.

The inventors conclude 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 and associated anxiety.

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

The MADRS item "Inner Tension" represents feelings of undefined discomfort, irritability, inner confusion, mental tension escalating into panic, fear, or distress. It is rated in terms of intensity, frequency, duration, and degree of reassurance required.

If the patient is calm and has only brief bouts of nervousness, the score is 0. If there are occasional feelings of irritability and vague discomfort, the score is 2. If there is constant nervousness or intermittent panic that the patient has difficulty controlling, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

In the above trial involving patients with TRD, the total score for the MADRS item “internal tension” for all 8 patients in the study group that received the individualized dosing regimen was 26 at baseline. After 2 hours, the score dropped to 11, which corresponds to an improvement of 15 points or 58%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 20 points or 77%. On the seventh day after treatment, the score dropped to 12, which corresponds to an improvement of 14 points or 54%.

In the 12 mg group, the total score for the MADRS item "internal tension" was 13 at baseline for all 4 patients. After 2 hours, the score dropped to 2, which corresponds to an improvement of 11 points or 85%. On the first day after treatment, the score dropped to 3, which corresponds to an improvement of 10 points or 77%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 8 points or 62%.

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

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

The clinical response in patients suffering from anxiety symptoms (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients suffering from anxiety symptoms (reflected by a decrease of at least 50% in the HAM-A score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety symptoms in a patient suffering from anxiety symptoms is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety symptoms in patients suffering from anxiety symptoms (as reflected by a HAM-A score of 7 or less) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety symptoms in patients suffering from anxiety symptoms (as reflected by a HAM-A score of 7 or less) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Psychomotor retardation

The key aspects observed in patients suffering from psychomotor retardation are decreased energy and activity and reduced motivation.

Psychomotor retardation involves a person's slower thinking and decreased body movement. Psychomotor impairment can result in noticeably slower physical and emotional responses.

Psychomotor retardation may be associated with a psychiatric or neurological disorder or some other medical condition.

Mental or neurological disorders that cause or are associated with psychomotor retardation include disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; 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 disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; chronic fatigue syndrome.

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

Measuring psychomotor retardation

Psychomotor retardation can be assessed by measuring various aspects. These can include, for example, various types of drawing tasks and tests, such as the Trail Making Test (TMT), the Digit Symbol Substitution Test (DSST), or the Gibson Spiral Maze Test (GSM), as well as other tests known in the art.

For example, in the line connection test (TMT), the subject must connect 25 circles containing numbers (TMT A) or numbers and letters (TMT B) in ascending order. The task requirements of TMT-B are similar, except that the subject must alternate between numbers and letters (1, A, 2, B, 3, C, etc.). Therefore, the test evaluates processing speed (TMT A) or cognitive flexibility (TMT B). The score of each part represents the amount of time required to complete the task.

Another test involving written motor skills is the Gibson spiral maze (GSM), which assesses only psychomotor speed and is not influenced by cognitive ability. To complete the GSM, subjects must correctly trace a spiral maze from the start to the end without touching the border lines.

The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of digit-symbol pairs and lists of numbers. Under each number, the subject should write down the corresponding symbol as quickly as possible. The score is determined by the number of symbols reported correctly within 90 seconds. Another example of a motor test is the finger tapping test.

Therefore, some tests combine measures of both motor and cognitive aspects of psychomotor retardation, whereas other tests assess only the motor aspects.

Speech analysis can serve as a further indicator of psychomotor retardation.

The main scales that can be used for assessment and measurement include the severity of psychomotor retardation, the Salpêtrière Slowness Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

The Salpêtrière Slowness Rating Scale (SRRS) was developed to assess cognitive and motor aspects through fifteen items. The first three indicators measure the quality of movement, especially stride length and the slowness of movements of the limbs, trunk, head and neck. The next three items focus on speech and include speech fluency, intonation and length of answers. Two items were designed to measure cognitive function objectively. These questions are based on interview dialogues and measure the patient's ability to approach and expand on topics. Further items are subjective and assess brooding, fatigue, interest level, time perception, memory and attention. The last item of the scale is related to the overall assessment of the patient's psychomotor slowness. Based on the severity of the symptoms presented, the items are scored from 0 (no symptoms) to 4 (severe), and the total score ranges from 0 to 60.

The Motor Agitation and Retardation Scale (MARS) assesses motor aspects only. It is designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five major physical categories: eyes, face, voice, limbs, and trunk, with a total of 19 items on the scale. Items in the eyes category include gaze direction, number of blinks, gaze, and eye movements. Items related to the face category include facial expression and facial expressivity. The voice category has items including volume, slurring, pitch, and onset time. Items under the limb category include movements of the hands, feet, and legs, stride length, slowness of movements, and tension in the hands. Items under the trunk category include posture, immobility, and axial movements. The severity of each item ranges from 1 to 4, with 4 being the most severe. Of the 19 items, 9 are related to motor agitation and 10 items assess motor retardation. The MARS scale allows for a rapid clinical assessment of motor signs.

Resting-state networking and psychomotor retardation

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by 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 networks of connections have been found to be impaired in a variety of disease states. Such disease states, including certain forms of psychomotor retardation, have been associated with altered functional connectivity within a specific resting-state network and/or between one or more regions in one or more additional resting-state 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 to be associated with psychomotor retardation and agitation in depressive disorders.

In many cases, the resting-state network involved in psychomotor retardation is affected by psychiatric or neurological disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; 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 disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

The resting-state network involved in psychomotor retardation is also affected by sleep disturbances such as insomnia. In fact, psychomotor retardation is associated with sleep impairment.

Treatment of psychomotor retardation and mental or nervous system disorders

According to the present invention, psychomotor retardation in patients suffering from mental disorders or nervous system disorders can be treated. In addition, psychomotor retardation occurring in patients suffering from sleep disorders (such as insomnia) can be treated.

In patients suffering from psychomotor retardation associated with another disorder detailed above, the treatment of psychomotor retardation according to the invention results in an improvement of the disorder associated with the psychomotor retardation.

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

Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and/or between resting-state networks. This disruption results in the resetting of pathological, poorly connected connections as the networks rewire. New, healthy functional connections are established, and this has lasting effects.

Therefore, according to the present invention, affecting these resting state networks through therapies as described herein will lead to improvement in psychomotor retardation, and if the patient being treated suffers from a psychiatric disorder or a neurological disorder, the disorder will also be improved; if the patient being treated suffers from a sleep disorder (such as insomnia), the sleep disorder (such as insomnia) will also be improved.

To further support the clinical utility of 5-MeO-DMT in patients suffering from psychomotor retardation, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in psychomotor retardation, which is also commonly observed in patients suffering from other disorders.

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

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. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as those related to psychomotor retardation) were associated with other disorders in which psychomotor retardation was based on similar altered functional connectivity within and/or between the somatomotor/sensorimotor networks, the visual network, the dorsal attention network, and the default mode network.

Multiple patients in the recruited cohort showed significant improvements, and this result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

More specifically, one aspect that can be treated by administering 5-MeO-DMT is psychomotor retardation. 5-MeO-DMT can be administered to a patient to reduce or eliminate psychomotor retardation in the patient.

The item in the MADRS scale that is particularly relevant to psychomotor retardation is “slouching,” which represents difficulty starting or slowness in initiating and performing daily activities.

A score of 0 means almost no difficulty in getting started and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and cannot do anything without help, the score is 6.

In the study group that received the individualized dosing regimen, the total score for the MADRS item “laziness” was 27 at baseline for all eight patients.

After 2 hours, the score dropped to 10, which corresponds to 17 points or 63% improvement. On the first day after treatment, the score dropped to 5, which corresponds to 22 points or 81% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 24 points or 89% improvement.

In the 12 mg group, the total score of the MADRS item "slouching" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 6 points or 38%. On the first day after treatment, the score dropped to 0, which corresponds to an improvement of 16 points or 100%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

Thus, the score of the scale item "slothiness", which is particularly relevant to psychomotor retardation, was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat psychomotor retardation in patients, especially those who also suffer from psychiatric or neurological disorders or sleep disorders (e.g. insomnia).

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

Social/emotional withdrawal or alienation

Symptoms such as anhedonia, emotional withdrawal, and affective apathy are categorized herein as social/emotional withdrawal or alienation. Reduced social engagement is another aspect associated with social/emotional withdrawal or alienation.

Anhedonia is the inability to experience pleasure. If the subjective ability to experience pleasure in daily activities is not reduced, the patient does not suffer from anhedonia. Anhedonia is mild if the pleasure obtained from normally pleasurable activities is slightly reduced, moderate if the pleasure obtained from normally pleasurable activities is significantly reduced or some pleasure obtained from isolated activities is preserved, or severe if pleasure cannot be experienced at all.

Anhedonia includes both consumptive (or liking) and anticipatory (or wanting) components. Consumptive hedonia refers to the “instant” pleasure experienced when a subject is directly involved in a pleasurable activity, while anticipatory hedonia refers to the pleasurable experience associated with a future activity.

Affective apathy characterizes the subjective feeling of a decrease in the intensity or range of feelings or emotions. If a decrease in the intensity or range of feelings or emotions is not felt, the subject does not exhibit affective apathy. Affective apathy is mild if the range of emotions is slightly reduced, or the range or intensity of feelings is temporarily reduced; moderate if the range or intensity of feelings is significantly reduced, but some emotions are retained, such as the inability to cry; and severe if the range of emotions is significantly and pervasively reduced, or the inability to experience usual emotions.

Emotional withdrawal or detachment refers to the inability or unwillingness to connect with others on an emotional level. For example, the BPRS contains an item related to emotional withdrawal, which is characterized by a deficit in the subject's ability to express emotion during the interview. According to the description of this BPRS item, emotional withdrawal is absent if there is no lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional seeming distracted, or a stiff smile, but spontaneously engaging with the interviewer most of the time. Mild emotional withdrawal is present if there is a lack of emotional engagement, as evidenced by an apparent failure to respond to comments, seeming distracted or lacking enthusiasm, but responding when approached by the interviewer. Emotional withdrawal is moderate if emotional engagement is absent during most of the interview, as the subject does not respond in detail, does not make eye contact, does not seem to care whether the interviewer is listening, or may be immersed in psychotic material. Alternatively, emotional withdrawal is moderate to severe if emotional engagement is absent during most of the interview. The severe form is present if the subject actively avoids emotional engagement, or if the subject often does not respond or responds with a yes/no answer or only with minimal emotional response. Affective withdrawal was considered extreme if the subject consistently avoided emotional engagement, did not respond or responded with a yes/no answer, or was likely to walk away during the interview or not respond at all.

Impaired social engagement characterizes the subjective report of decreased social and interpersonal engagement or interaction. If there is no report of decreased social and interpersonal engagement or interaction, then there is no impaired social engagement. Impaired social engagement is mild if social engagement is slightly impaired but social or interpersonal functioning is not impaired; moderate if social engagement is markedly impaired and is accompanied by some functional sequelae, such as avoidance of some social engagements or conversations; and severe if social interactions are markedly impaired or almost all forms of social contact are avoided, such as refusing to answer the phone or see friends or family.

Social/emotional withdrawal or alienation may be related to a psychiatric or neurological disorder or some other medical condition.

Mental or neurological disorders that cause or are associated with social/emotional withdrawal or alienation include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, 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); post-traumatic stress disorder These disorders include post-traumatic 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 disorder (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); 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 with sleep disorders such as insomnia.

Social/emotional withdrawal or alienation may also occur in patients with medical health conditions that result in associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

Measuring social/emotional withdrawal or alienation

Social/emotional withdrawal or alienation (generally referred to herein as social/emotional withdrawal) or its individual aspects, such as anhedonia, emotional withdrawal and emotional apathy, can be assessed by different tools, such as questionnaires or scales.

Questionnaires assess a patient's mental state based on observations by the patient, a caregiver, or the clinician who fills out the questionnaire. Questionnaires used to assess patients for specific psychiatric or neurological disorders may include items related to social/emotional withdrawal or alienation.

The Snaith-Hamilton Hedonic Scale (SHAPS) is a 14-item scale that measures anhedonia, or the inability to experience pleasure. The items cover areas including: social interaction, food and drink, sensory experiences, and interests/pastures. A score of 2 or less constitutes a "normal" score, while a score of 3 or more is defined as an "abnormal" score. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Any "disagree" response is scored as one point, and any "agree" response is scored as 0. Therefore, the final score range is 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. A high degree of internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression, but it is also frequently used to assess anhedonia in other patient groups.

In principle, SHAPS uses 14 hypothetically formulated items to measure hedonic tone over the past few days. However, due to the hypothetical nature of the items, appropriately shorter recall periods can also be applied to earlier assessment time points.

Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS) can be used to assess anhedonia, which measures interest, motivation, effort, and consumptive pleasure in four areas (hobbies, food/beverages, social activities, and sensory experiences). The scale includes 17 items that assess current state anhedonia. The DARS is rated on a five-point Likert scale, from 0 (not at all) to 4 (very much), with higher values indicating less anhedonia. The total score for all items is between 0 and 68. For the four hedonic areas, namely hobbies (four items, total score 0-16), food/beverages (four items, total score 0-16), social activities (four items, total score 0-16), and sensory experiences (5 items, total score 0-20), participants were asked to provide two or three of their own favorite examples.

The Personality Inventory for DSM-5 (PID-5) - Adult is a 220-item self-rating personality trait assessment inventory for adults 18 years and older. It assesses 25 personality trait facets, including anhedonia, anxiety, attention seeking, callousness, deceitfulness, depression, distractibility, eccentricity, affective instability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, manipulativeness, perceptual dysregulation, stubbornness, emotional restriction, rigid perfectionism, risk-taking, separation insecurity, submissiveness, suspiciousness, unusual beliefs and experiences, and withdrawal, with each trait facet consisting of 4 to 14 items.

The Anhedonia trait facet contains items 1, 23, 26, 30R, 124, 155R, 157, 189 (reverse-scored items are marked with the letter "R"), the Withdrawal trait facet contains items 10, 20, 75, 82, 136, 146, 147, 161, 182, 186, and the Intimacy Avoidance trait facet contains items 89, 97R, 108, 120, 145, 203. These three trait facets can be combined to produce a broader trait domain designated Distant.

The measure is completed by the individual prior to visiting a clinician. Each item asks the individual to rate how well the item describes him or her overall.

Each item in the measure was rated on a 4-point scale. The response categories for the items were: 0 = very false or often false; 1 = sometimes or somewhat false; 2 = sometimes or somewhat true; 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 entering the scale score calculation.

The scores of the items within each trait facet should be added together and entered into the appropriate raw facet score box. In addition, clinicians are also asked to calculate and use the average score for each facet and domain. The average score reduces the total score and the score of each domain to a 4-point scale, which enables clinicians to think about the individual's personality dysfunction relative to the observed norm. The average 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 are rated as "sometimes or a little true", the average facet score will be 16/8=2, indicating moderate anhedonia). The average domain score is calculated by adding the 3 facet scores that contribute primarily to a particular domain and then averaging them. For example, if the average facet scores for anhedonia, avoidance of intimacy, and withdrawal (the scale that primarily indexes alienation) are all 2, the sum of these scores will be 6, and the average domain score will be 6/3=2. The higher the average score, the more severe the dysfunction in a particular personality trait facet or domain.

High scores on aspects or domains may indicate significant and problematic areas for the individual receiving care, who may require further assessment, treatment, and follow-up.

Resting-state networking and social/emotional withdrawal or alienation

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by 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 networks of connectivity have been found to be impaired in a variety of disease states. Such disease states, including certain forms of social/emotional withdrawal or alienation, have been associated with altered functional connectivity within a specific resting-state network and/or between one or more regions in one or more additional resting-state networks.

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

In addition, emotional alienation in adult psychosis is associated with structural abnormalities in the dorsal DMN. Because the dorsal DMN has functions associated with psychosis, it is particularly interesting in the development of psychosis. Specifically, the dorsal DMN and its connected areas (medial prefrontal cortex and posterior cingulate cortex (PCC)) support emotional, social and moral processing. In adult psychosis, microstructural abnormalities within the dorsal DMN are associated with the emotional and interpersonal differences that define the disorder.

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

In many cases, RSNs involving social/emotional withdrawal or alienation are affected by psychiatric or neurological disorders, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, 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); post-traumatic 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 disorder (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); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

Resting-state networks involved in social/emotional withdrawal or disengagement can also be affected by psychiatric or neurological disorders as a result of certain medical health conditions, such as traumatic brain injury (TBI).

Resting-state networks involved in social/emotional withdrawal or detachment are also affected by sleep disturbances such as insomnia. In fact, social/emotional withdrawal or detachment is associated with sleep impairment.

Treating social/emotional withdrawal or alienation and psychiatric or neurological disorders

According to the present invention, social/emotional withdrawal or alienation occurring in patients suffering from psychiatric disorders or neurological disorders can be treated. In addition, social/emotional withdrawal or alienation occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

In patients suffering from social/emotional withdrawal or alienation associated with another disorder detailed above, treatment of social/emotional withdrawal or alienation according to the invention results in an improvement of the disorder associated with the social/emotional withdrawal or alienation.

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

Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and/or between resting-state networks. This disruption results in the resetting of pathological, poorly connected connections as the networks rewire. New, healthy functional connections are established, and this has lasting effects.

Thus, according to the present invention, influencing these networks through therapies as described herein will result in improved social/emotional withdrawal or alienation, and if the patient being treated suffers from a psychiatric or neurological disorder, the disorder will also be improved; if the patient being treated suffers from a sleep disorder (e.g., insomnia), the sleep disorder (e.g., insomnia) will also be improved.

To further support the clinical utility of 5-MeO-DMT in patients suffering from social/emotional withdrawal or detachment, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in social/emotional withdrawal or detachment, which is also commonly observed in patients suffering from other disorders.

The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). Although TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for other disorders associated with social/emotional withdrawal or alienation.

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. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as items related to social/emotional withdrawal or alienation) were associated with other disorders, in which social/emotional withdrawal or alienation was based on similarly altered functional connectivity within and/or between the default mode network, the salience network, the dorsal attention network, the somatomotor network, and the visual network.

Multiple patients in the recruited cohort showed significant improvements, a result that confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

More specifically, one aspect that can be treated by administering 5-MeO-DMT is social/emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and/or emotional apathy. Another aspect of treatment is reduced social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's social/emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and/or emotional apathy. Additionally, reduced social engagement is improved, i.e., reduced or eliminated.

The MADRS scale item “Anorexia of Sensation”, which is particularly relevant to social/emotional withdrawal or detachment, represents the subjective experience of reduced interest in one’s surroundings or in activities that would normally bring pleasure. Reduced ability to respond adequately emotionally to situations or people.

A score of 0 indicates normal interest in one's surroundings and other people, and a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 is considered a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional paralysis, the inability to feel anger, sadness, or pleasure, and a complete and even painful loss of affection for friends and family.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to an improvement of 24 points or 67%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 34 points or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 30 points or 83%.

In the 12 mg group, the total score for the MADRS item "loss of sensation" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%.

BPRS items that are particularly relevant to social/emotional withdrawal or alienation are “emotional withdrawal” and “emotional blunting.”

The BPRS item "emotional withdrawal" is related to the patient's deficits in expressing emotions during the interview. Possible scores are:

1- No emotional withdrawal.

2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional absent-mindedness or a stiff smile, but most of the time spontaneously interacting with the interviewer.

3 - Mild. Lack of emotional engagement, as evidenced by an apparent failure to respond to comments, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

4 - Moderate. Emotional contact is absent during most of the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be immersed in the psychotic material.

5 - Moderately severe. Same as 4, but emotional contact was absent during most of the interview.

6 - Severe. Actively avoids emotional engagement. Often does not respond or responds with yes/no answers (not just due to persecutory delusions). Or responds with only minimal emotion.

7 - Extreme. Consistently avoids emotional engagement. Does not respond or responds with yes/no answers (not just due to persecutory delusions). May walk away during the interview or not respond at all.

The total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

In the 12 mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 2 points or 15%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 7 points or 54%.

The BPRS item “Blunting of Emotion” involves a restricted range of emotional expressiveness in the face, voice, and gestures, as well as apparent apathy or indifference even when discussing painful topics. Possible scores are:

1- No emotional blunting.

2 - Very Mild. Emotional range is slightly suppressed or reserved, but facial expressions and voice intonation are appropriate and within normal range.

3 - Mild. Overall reduced, suppressed or reserved emotional range, without many spontaneous and appropriate emotional responses. Slightly monotonous tone of voice.

4 - Moderate. The range of emotions is markedly diminished, and except in rare cases, the patient does not show emotion, smile, or respond to distressing topics. The tone of voice or spontaneous movements is markedly reduced. Displays of emotion or gestures usually result in a return of emotion that is cold.

5 - Moderate to severe. The range of emotions is very diminished, the patient does not show emotion, smile, or respond to painful topics, and the facial expression does not change often except for minimal, few gestures. The tone of voice is monotonous most of the time.

6 - Severe. Very little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression does not change. Voice intonation is monotonous most of the time.

7 - Extreme. There is little emotional range or expression, and movements are stiff. The tone of voice is monotonous at all times.

The total score for the BPRS item "blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

In the 12 mg group, the total score for the BPRS item "blunting" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 3 points or 27%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 5 points or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 6 points or 55%.

Thus, the scores of the scale items particularly related to social/emotional withdrawal or alienation, namely "loss of sensation" (MADRS), "emotional withdrawal" (BPRS) and "blunted affect" (BPRS) were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat social/emotional withdrawal or alienation in patients, especially those who also suffer from psychiatric disorders or neurological disorders or sleep disorders (such as insomnia).

Thus, according to the present invention, treatment of a patient suffering from social/emotional withdrawal or alienation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social/emotional withdrawal or alienation.

Negative thinking

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

Helplessness and hopelessness (also referred to simply as helplessness and hopelessness) characterize a subjective feeling of pessimism or hopelessness about the future, of being unable to cope, or of having lost control. If the patient does not have such feelings, then helplessness and hopelessness are not present. Helplessness and hopelessness are mild if there are occasional mild feelings of being unable to cope as usual or of being pessimistic; moderate if the patient often feels unable to cope or has significant feelings of helplessness or hopelessness that sometimes disappear; or severe if there is a marked and persistent feeling of pessimism, helplessness, or hopelessness.

Worthlessness (also simply called worthlessness) characterizes subjective feelings or thoughts of decreased self-worth or self-worth. If the patient does not have such feelings, then worthlessness is not present. Worthlessness can be mild, with a slightly decreased sense of self-worth; moderate, with some thoughts of worthlessness and decreased self-worth; or severe, with marked, pervasive, or persistent feelings of worthlessness, such as a feeling that others are better off without them and an inability to appreciate positive qualities.

Guilt (also simply called guilt) characterizes a subjective feeling of self-blame, failure, or regret for past real or imagined mistakes. If the patient does not have such feelings, guilt is not present. Guilt is mild if there is a slight decrease in self-esteem or increased self-criticism; moderate if there are significant thoughts of failure, self-criticism, inability to cope, or ruminations about past failures and their effects on others; and if excesses are recognized; or severe if there is obvious, pervasive, or persistent guilt, such as a feeling that one deserves to be punished; or if excesses are not clearly recognized.

Negative thinking may be associated with a mental or neurological disorder or some other medical condition.

Mental or neurological disorders that cause or are associated with negative thinking include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, 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); post-traumatic 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; dementia, such as Alzheimer's disease dementia (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

Negative thinking may also occur in patients with sleep disorders such as insomnia.

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

Measuring Negative Thinking

Negative thinking or its individual aspects, such as worthlessness, helplessness and hopelessness, and guilt, can be assessed by different instruments, such as questionnaires or scales.

Questionnaires assess a person's mental state based on observations by the person, a caregiver, or a clinician who fills out the questionnaire. Questionnaires used to assess a person for specific mental or neurological disorders may include items related to negative thinking.

Instruments that assess aspects related to negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Scale-Expanded (PANAS-X), or the State Hope Scale (SHS).

The State Shame and Guilt Scale (SSGS) is a self-rating scale of current (state) shame and guilt experiences. It includes two subscales, the Shame subscale and the Guilt subscale. The Shame subscale includes Items 1, 3, 5, 7, 9. The Guilt subscale includes Items 2, 4, 6, 8, 10. All items are scored positively and rated on a 5-point Likert scale. The scale contains some statements that may or may not describe the patient's current feelings. The higher the score, the stronger the shame or guilt.

The Positive and Negative Affect Scale-Extended (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, happiness, confidence, concentration, and calmness. Thus, the PANAS-X provides two different levels of emotion measurement. The basic negative affect scales are fear, hostility, guilt, and sadness, while the guilt scale covers six items: guilty, ashamed, blameworthy, angry at myself, disgusted with myself, and dissatisfied with myself. Each answer should be scored on the following scale: 1 = very slightly or not at all; 2 = a little; 3 = moderately; 4 = quite a bit; or 5 = extremely. However, researchers facing tighter time constraints can only select and evaluate the scales that are most relevant to their study.

The stronger the guilt, the higher the score reflected on the guilt scale.

The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item scale in 10 minutes or less. This scale consists of many words and phrases that describe different feelings and emotions. Although it should indicate the extent to which the patient has felt this way over the past few weeks, trait scores on the PANAS-X scales, including "now," "today," and "past few days," were found to be stable over time, indicating that appropriately shorter recall periods can be used.

The State Hope Scale (SHS) has three agency items and three pathway items, and respondents describe themselves in terms of their "current" situation. The agency subscale score is calculated by adding items 2, 4, and 6, which are related to the perceived ability to use personal pathways to achieve desired goals; the pathway subscale score is calculated by adding items 1, 3, and 5, which are related to the thinking used to identify possible ways to achieve goals. The total State Hope Scale score is calculated by adding the three agency items and the 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 HAM-D, MADRS, BPRS or BDRS, wherein the relevant items of said scales can be generally applied to assess negative thinking or aspects thereof.

Resting-state networks and negative thinking

Brain processes can be studied by 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 images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

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

Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been 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 networks of connectivity have been found to be impaired in various disease states. Such disease states, including certain forms of negative thinking, have been associated with altered functional connectivity within a specific resting-state network and/or between one or more regions in one or more additional resting-state networks.

Major depressive disorder (MDD) is a disorder characterized by high levels of negative affect and lower levels of positive affect. More specifically, lower levels of positive affect (such as hope) mean higher levels of hopelessness and higher levels of negative affect (such as guilt). MDD has always been the focus of research in the field of rs-fMRI, showing that MDD is a disorder characterized by extensive network dysfunction. This dysfunction mainly occurs in networks and regions related to emotion regulation. These networks and regions include the default mode network (DMN), the salience network, the affect network, and the prefrontal cortex. Therefore, different aspects of negative thinking may be associated with abnormal resting state networks.

Patients with repetitive negative thinking (RNT) have been reported to have functional impairments in resting-state networks, including altered connectivity of the left executive control network and the anterior salience network with the ventral default mode network.

Thus, patients suffering from negative thinking showed altered functional connectivity within and/or between resting-state networks compared to age-matched healthy controls. Alterations were observed within and/or between at least the default mode network, executive control network, salience network, affect network, and prefrontal cortex.

In many cases, RSNs involving negative thinking are affected by psychiatric or neurological disorders, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, 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); post-traumatic 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; dementia, such as Alzheimer's disease dementia (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

Resting state networks involved in negative thinking can also be affected by psychiatric or neurological disorders as a result of certain medical health conditions, such as traumatic brain injury (TBI).

The resting-state network involved in negative thinking is also affected by sleep disturbances such as insomnia. In fact, negative thinking is associated with impaired sleep.

Treatment of negative thinking and mental or neurological disorders

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

In a patient suffering from negative thoughts associated with another disorder detailed above, treatment of negative thoughts according to the invention results in an improvement in the disorder associated with the negative thoughts.

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

Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and/or between resting-state networks. This disruption results in the resetting of pathological, poorly connected connections as the networks rewire. New, healthy functional connections are established, and this has lasting effects.

Therefore, according to the present invention, influencing these networks through therapies as described herein will lead to improvements in negative thinking, and if the patient being treated suffers from a psychiatric or neurological disorder, the disorder will also be improved; if the patient being treated suffers from a sleep disorder (such as insomnia), the sleep disorder (such as insomnia) will also be improved.

To further support the clinical utility of 5-MeO-DMT in patients suffering from negative thinking, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in negative thinking, which is also commonly observed in patients suffering from other disorders.

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

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. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items, such as those related to negative thinking, were associated with other disorders in which negative thinking was based on similar altered functional connectivity within and/or between the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

Multiple patients in the recruited cohort showed significant improvements, and this result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

More specifically, one aspect that can be treated by administering 5-MeO-DMT is negative thinking, particularly feelings of worthlessness, helplessness and hopelessness, and/or guilt. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's negative thinking, particularly feelings of worthlessness, helplessness and hopelessness, and/or guilt.

The MADRS scale item that is particularly related to negative thinking is “pessimistic thinking,” which represents thoughts of guilt, inferiority, self-blame, sin, regret, and destructiveness.

If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score refers to persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of annihilation, remorse, or irreparable guilt, and absurd and unshakable self-accusations, the score is 6.

In the study group that received the individualized dosing regimen, the total score for the MADRS item “pessimistic thoughts” was 28 at baseline for all eight patients.

After 2 hours, the score dropped to 7, which corresponds to 21 points or 75% improvement. On the first day after treatment, the score dropped to 4, which corresponds to 24 points or 86% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 25 points or 89% improvement.

In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all four patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%.

On day 7 after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

A BPRS item that is particularly relevant to negative thinking is "Guilt." This item is related to excessive focus on or regret for past behavior. Possible scores are:

1- No guilt.

2 - Very Mild. Worries about disappointing someone or failing at something, but is not distracted. Can easily shift thoughts to other things.

3-Mild. Worry about disappointing someone or failing at something and tends to be distracted. Tends to express guilt to others.

4 - Moderate. Obsessively dwells on guilt, wrongdoing, or hurting others by something they did or did not do, but can easily shift their focus to other things.

5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something; can shift focus to other things but only with great effort. Not delusional.

6 - Severe; paranoid guilt or unreasonable self-blame that is highly disproportionate to the circumstances. Moderate absent-mindedness present.

7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on the delusion.

In the study group that received the individualized dosing regimen, the total score for the BPRS item “guilt” was 34 at baseline for all eight patients.

After 3 hours, the score dropped to 14, which corresponds to a 20-point or 59% improvement. On day 1 after treatment, the score dropped to 11, which corresponds to a 23-point or 68% improvement. On day 7 after treatment, the score dropped to 10, which corresponds to a 24-point or 71% improvement.

In the 12 mg group, the total score of the BPRS item “guilt” was 18 at baseline for all 4 patients.

After 3 hours, the score dropped to 9, which corresponds to 9 points or 50% improvement. On the first day after treatment, the score dropped to 5, which corresponds to 13 points or 72% improvement. On the seventh day after treatment, the score dropped to 5, which corresponds to 13 points or 72% improvement.

Therefore, the score of the MADRS scale item "pessimistic thoughts" which is particularly related to negative thinking was significantly improved, and the score of the BPRS item "guilt" was also significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat negative thinking in patients, especially those who also suffer from mental disorders or nervous system disorders or sleep disorders (such as insomnia).

Thus, 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.

Mother function

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

The first year after childbirth, in particular, is a critical window for both mother and child. In most cases, the mother is the primary caregiver and is therefore responsible for most tasks related to infant care.

Maternal functioning includes aspects of maternal competence related to interaction with the infant and maternal self-care.

Maternal functioning, including the emotional aspects of motherhood, is also important for the child’s development. In fact, the quality of mother-child interactions in the first year after birth can influence infant development. High levels of maternal functioning may be associated with positive infant developmental outcomes. Likewise, impaired functioning in the postpartum period may hinder optimal infant development.

The Barkin Index of Maternal Function (BIMF) is designed to measure function within one year after childbirth. The BIMF is a 20-item self-report function measurement. Each item is scored from 0 to 6, making the maximum total score 120 points. The higher the score, the better the assessment of maternal function.

BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and regulation.

BIMF scores of 95 or less are considered herein to represent mild impairment of maternal function, scores of 80 or less are considered herein to represent impaired maternal function, and scores of 65 or less are considered herein to represent severely impaired maternal function. The present invention particularly allows for improvement in maternal function in patients with a score of 80 or less before treatment, and even in patients with a score of 65 or less.

As described above, the present invention allows the treatment of patients suffering from psychiatric or neurological disorders. Said treatment not only leads to a reduction in the score assessing the severity of depression, but also improves maternal functioning, as discussed in detail below.

To further support the clinical utility of 5-MeO-DMT in patients suffering from psychiatric or neurological disorders, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in aspects of illness that are also commonly observed in patients suffering from psychiatric or neurological disorders. The inventors particularly noted improvements in various symptoms and combinations of symptoms that the inventors determined may be related to maternal function.

This data is derived from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). A more recent trial conducted on patients suffering from postpartum depression confirmed these results (see the Examples section below).

In the TRD clinical trial, 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 that received a single 12 mg dose and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience, were of interest.

The data collected included assessments of the treated patients on several scales, including the Montgomery Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that several sub-score items were particularly relevant to patients with mental or neurological disorders and were related to maternal functioning.

Multiple patients in the recruited cohort demonstrated significant improvements in one or more of these subscores, and the results confirm the inventors' findings that 5-MeO-DMT is a compound suitable for treating patients with psychiatric or neurological disorders and for improving maternal function in those patients.

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

Thus, treatment according to the invention reduces or eliminates (or ameliorates or eliminates) one aspect of the disease.

If the aspect is assessed according to the MADRS scale, there is at least one point improvement (reduction) or the patient is completely relieved (eliminated) after treatment, i.e. the corresponding aspect score is 0.

If the aspect is assessed according to the BPRS scale, there is at least one point improvement (reduction) or the patient is completely relieved (eliminated) after treatment, that is, the corresponding aspect score is 1.

The clinical response can also be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and/or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and/or to 0 points.

The inventors further believe that the improvements observed in certain MADRS items will translate into improvements in maternal functioning.

Particularly relevant MADRS items are discussed in more detail below.

The MADRS item "Inner Tension" represents feelings of undefined discomfort, irritability, inner confusion, mental tension escalating into panic, fear, or distress. It is rated in terms of intensity, frequency, duration, and degree of reassurance required.

If the patient is calm and has only brief bouts of nervousness, the score is 0. If there are occasional feelings of irritability and vague discomfort, the score is 2. If there is constant nervousness or intermittent panic that the patient has difficulty controlling, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

The inventors have determined that an increase in the score of the MADRS item "internal tension" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infants and maternal self-care). As assessed by BIMF, an increase in the score of the MADRS item "internal tension" impairs mother-child interaction and maternal psychological health.

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

In the above trial involving patients with TRD, the total score for the MADRS item “internal tension” for all 8 patients in the study group that received the individualized dosing regimen was 26 at baseline. After 2 hours, the score dropped to 11, which corresponds to an improvement of 15 points or 58%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 20 points or 77%. On the seventh day after treatment, the score dropped to 12, which corresponds to an improvement of 14 points or 54%.

In the 12 mg group, the total score for the MADRS item "internal tension" was 13 at baseline for all 4 patients. After 2 hours, the score dropped to 2, which corresponds to an improvement of 11 points or 85%. On the first day after treatment, the score dropped to 3, which corresponds to an improvement of 10 points or 77%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 8 points or 62%.

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

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

Improvements in internal tension, as reflected by reductions in Clinical Global Impression-Severity (CGI-S) scores, occurred no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in internal tension (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in inner tension (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of inner tension achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as 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.

As intrapersonal tension may also influence other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "internal tension" item of the MADRS will additionally contribute to the overall improvement in maternal functioning.

The MADRS item “sluggishness” represents difficulty getting started or slowness in initiating and performing daily activities.

A score of 0 means almost no difficulty in getting started and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and cannot do anything without help, the score is 6.

The inventors have determined that an increase in the score of the MADRS item "lazy" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score of the MADRS item "lazy" impairs infant care, self-care, psychological health, management and regulation.

Conversely, improvements on this MADRS item led to improvements in maternal functioning, particularly in the BIMF functional domains of infant care, self-care, psychological well-being, management, and regulation.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "slouching" for all eight patients was 27 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 17 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 22 points or 81%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 24 points or 89%.

In the 12 mg group, the total score of the MADRS item "slouching" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 6 points or 38%. On the first day after treatment, the score dropped to 0, which corresponds to an improvement of 16 points or 100%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

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

The improvement in laziness is reflected at least in an improvement in the score of the MADRS item laziness at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in laziness, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

An improvement in laziness (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in laziness (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of laziness achieved by treating patients with mental or nervous system disorders not only leads to a reduction in the total score of MADRS, but also leads to an improvement in maternal function, which is reflected in an increase in BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in BIMF score will also be observed on the first day, such as 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. Since laziness can also affect other aspects of mental or nervous system disorders, the inventors concluded that the observed improvement in the "laziness" item in MADRS will additionally contribute to the overall improvement in maternal function.

The MADRS item "Anesthesia" represents the subjective experience of reduced interest in one's surroundings or in activities that normally provide pleasure. Reduced ability to respond adequately emotionally to the environment or people.

A score of 0 indicates normal interest in one's surroundings and other people, and a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 is considered a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional paralysis, the inability to feel anger, sadness, or pleasure, and a complete and even painful loss of affection for friends and family.

The inventors have determined that an increase in the score of the MADRS item "sensory loss" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score of the MADRS item "sensory loss" impairs mother-child interaction and psychological health.

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

In the study group that received the individualized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to an improvement of 24 points or 67%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 34 points or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 30 points or 83%.

In the 12 mg group, the total score for the MADRS item "loss of sensation" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%.

The inventors conclude that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve reduction or elimination of sensory deficits.

The improvement in anesthesia is reflected in at least an improvement in the score for the MADRS item anesthesia at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in anesthesia, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in anesthesia (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sensory loss (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of sensory loss achieved by treating patients with mental or nervous system disorders will not only result in a reduction in the total score of the MADRS, but also in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed at day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 13 Since sensory loss can also affect other aspects of mental or nervous system disorders, the inventors concluded that the observed improvement in the "sensory loss" item in the MADRS will additionally contribute to the overall improvement in maternal function.

The MADRS item “difficulty concentrating” represents difficulty collecting one’s thoughts, resulting in an inability to concentrate.

If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty collecting one's thoughts, the score is 2. If the difficulty concentrating and maintaining thoughts leads to reduced ability to read or hold a conversation, the score is 4. If the patient cannot read or hold a conversation easily, the score is 6.

The inventors have determined that increased scores on the MADRS item "Difficulty Concentrating" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "Difficulty Concentrating" impair infant care and management.

Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domain infant care and/or management.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "Difficulty concentrating" was 30 at baseline for all eight patients. After 2 hours, the score dropped to 11, which corresponds to an improvement of 19 points or 63%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 29 points or 97%. On the seventh day after treatment, the score dropped to 9, which corresponds to an improvement of 21 points or 70%.

In the 12 mg group, the total score for the MADRS item "difficulty concentrating" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 14 points or 88%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to reduce or eliminate difficulty concentrating.

The improvement in difficulty concentrating is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in difficulty concentrating, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in difficulty concentrating (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in difficulty concentrating (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of difficulty concentrating achieved by treating patients with mental or nervous system disorders not only results in a reduction in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed at 7 days, 14 days, and/or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

As difficulty concentrating may also affect other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "difficulty concentrating" item in the MADRS will additionally contribute to the overall improvement in maternal functioning.

The MADRS item “pessimistic thoughts” represents thoughts of guilt, inferiority, self-blame, sin, regret, and destructiveness.

If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score refers to persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of annihilation, remorse, or irreparable guilt, and absurd and unshakable self-accusations, the score is 6.

The inventors have determined that increased scores on the MADRS item "pessimistic thoughts" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "pessimistic thoughts" impair psychological health, social support and management.

Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, social support, and/or management.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "pessimistic thoughts" for all eight patients was 28 at baseline. After 2 hours, the score dropped to 7, which corresponds to an improvement of 21 points or 75%. On the first day after treatment, the score dropped to 4, which corresponds to an improvement of 24 points or 86%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 25 points or 89%.

In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

The inventors conclude that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of pessimistic thoughts.

The improvement in pessimistic thoughts is reflected in at least an improvement in the score of the MADRS item pessimistic thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in pessimistic thoughts, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurred no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in pessimistic thoughts (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in pessimistic thoughts (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of pessimistic thoughts achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total score of MADRS, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

As negative thoughts may also affect other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "negative thoughts" item of the MADRS will additionally contribute to the overall improvement in maternal functioning.

The MADRS item "Sleep reduction" represents the experience of a decrease in sleep duration or depth compared to the subject's normal pattern when healthy.

When the subject sleeps normally, the score is 0. A score of 2 reflects mild difficulty falling asleep or slightly reduced, shallow or intermittent sleep. A score of 4 means reduced or interrupted sleep of at least two hours. A score of 6 means less than two or three hours of sleep.

The inventors have determined that an increase in the score for the MADRS item "Sleep reduction" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score for the MADRS item "Sleep reduction" impairs self-care, psychological health and management.

Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and/or management.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score dropped to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score dropped to 9, which corresponds to an improvement of 16 points or 64%.

In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve reduction or elimination of sleep loss.

Reduction or elimination of sleep loss is reflected in at least an improvement in the score of the MADRS item sleep loss 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.

Improvement in sleep loss, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in sleep loss (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sleep loss (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of sleep loss achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 24 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

As sleep reduction may also affect other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "sleep reduction" item of the MADRS will additionally contribute to an overall improvement in maternal functioning.

Another aspect of a mental or nervous system disorder that can be treated by administering 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a patient with a mental or nervous system disorder to reduce or eliminate suicidal ideation in the patient.

In the above-mentioned clinical studies involving 5-MeO-DMT administration, the MADRS item “suicidal thoughts” was assessed, among others.

"Suicidal ideation" represents a feeling that life is not worth living, that a natural death is desirable, suicidal thoughts, and/or preparations for suicide. Suicide attempts themselves should not influence the rating of this MADRS item.

A score of 0 means that the patient enjoys life. If the patient with a mental or neurological disorder feels tired of life and/or has only brief suicidal thoughts, the score is 2. A score of 4 means that the patient feels that death would be better, suicidal thoughts are common and suicide is considered a possible solution, but the patient has no specific plan or intention. If the patient has a clear suicide plan and/or is actively preparing for it, the score is 6.

This MADRS scale item is particularly relevant to suicidal ideation.

The inventors have determined that increased scores on the MADRS item "suicidal thoughts" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "suicidal thoughts" impair self-care, psychological health and management.

Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and/or management.

In the study group that received the individualized dosing regimen, the total score for the MADRS item "suicidal thoughts" for all eight patients was 11 at baseline. After 2 hours, the score dropped to 3, which corresponds to an improvement of 8 points or 73%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 10 points or 91%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 8 points or 73%.

In the 12 mg group, the total score for the MADRS item "suicidal thoughts" was 8 at baseline for all 4 patients. After 2 hours, the score dropped to 3, which corresponds to an improvement of 5 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 3 points or 38%. On the seventh day after treatment, the score dropped to 7, which corresponds to an improvement of 1 point or 13%.

Thus, the score of the scale item "suicidal thoughts", which is particularly relevant to suicidal ideation, was significantly improved, at least in the patients on the individualized dosing regimen. The inventors conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with psychiatric or neurological disorders.

Thus, according to the present invention, treatment of a patient suffering from a psychiatric or neurological disorder suffering from suicidal ideation may reduce or eliminate suicidal ideation.

Reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

If the patient suffers from suicidal ideation, improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at 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; 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 (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in suicidal ideation (assessed as at least a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in suicidal ideation (assessed as a decrease in the CGI-S score or at least as a "much improved" score in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of suicidal thoughts achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

As suicidal thoughts may also affect other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "suicidal thoughts" item of the MADRS will additionally contribute to an overall improvement in maternal functioning.

The BPRS item "emotional withdrawal" is related to the patient's deficits in expressing emotions during the interview. Possible scores are:

1- No emotional withdrawal.

2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional absent-mindedness or a stiff smile, but most of the time interacting spontaneously with the interviewer.

3 - Mild. Lack of emotional engagement, as evidenced by an apparent failure to respond to comments, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

4 - Moderate. Emotional contact is absent during most of the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be immersed in the psychotic material.

5 - Moderately severe. Same as 4, but emotional contact was absent during most of the interview.

6 - Severe. Actively avoids emotional engagement. Often does not respond or responds with yes/no answers (not just due to persecutory delusions). Or responds with only minimal emotion.

7 - Extreme. Consistently avoids emotional engagement. Does not respond or responds with yes/no answers (not just due to persecutory delusions). May walk away during the interview or not respond at all.

The inventors have determined that increased scores on the BPRS item "emotional withdrawal" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "emotional withdrawal" impair psychological health, mother-child interaction and social support.

Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, mother-child interaction, and/or social support.

In the study group that received the individualized dosing regimen, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

In the 12 mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 2 points or 15%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 7 points or 54%.

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

Reduction or elimination of affective withdrawal is reflected in at least an improvement in the score of the BPRS item affective withdrawal at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in affective withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in affective withdrawal (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in affective withdrawal (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of emotional withdrawal achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total BPRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

Since emotional withdrawal may also influence other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvement in the "emotional withdrawal" item of the BPRS will additionally contribute to the overall improvement in maternal functioning.

The BPRS item “Blunting of Emotion” involves a restricted range of emotional expressiveness in the face, voice, and gestures, as well as apparent apathy or indifference even when discussing painful topics. Possible scores are:

1- No emotional blunting.

2 - Very Mild. Emotional range is slightly suppressed or reserved, but facial expressions and voice intonation are appropriate and within normal range.

3 - Mild. Overall reduced, suppressed or reserved emotional range, without many spontaneous and appropriate emotional responses. Slightly monotonous tone of voice.

4 - Moderate. The range of emotions is markedly diminished, and except in rare cases, the patient does not show emotion, smile, or respond to distressing topics. The tone of voice or spontaneous movements is markedly reduced. Displays of emotion or gestures usually result in a return of emotion that is cold.

5 - Moderate to severe. The range of emotions is very diminished, the patient does not show emotion, smile, or respond to painful topics, and the facial expression does not change often except for minimal, few gestures. The tone of voice is monotonous most of the time.

6 - Severe. Very little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression does not change. Voice intonation is monotonous most of the time.

7 - Extreme. There is little emotional range or expression, and movements are stiff. The tone of voice is monotonous at all times.

The inventors have determined that increased scores on the BPRS item "emotional blunting" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "emotional blunting" impair psychological health and mother-child interaction.

Conversely, improvements on this BPRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains psychological well-being and/or mother-child interaction.

The total score for the BPRS item "blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

In the 12 mg group, the total score for the BPRS item "blunting" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 3 points or 27%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 5 points or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 6 points or 55%.

The inventors conclude that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of affective blunting.

Reduction or elimination of blunting is reflected in at least an improvement in the score of the BPRS item blunting at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; 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 (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in affective blunting (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in affective blunting (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of blunted affect achieved by treating patients with mental or nervous system disorders not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as 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.

Since blunting of affect may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "blunting of affect" item of the BPRS would additionally contribute to the overall improvement in maternal functioning.

The BPRS item “Guilt” is related to excessive concern or regret about past behavior. Possible scores are:

1- No guilt.

2 - Very Mild. Worries about disappointing someone or failing at something, but is not distracted. Can easily shift thoughts to other things.

3-Mild. Worry about disappointing someone or failing at something and tends to be distracted. Tends to express guilt to others.

4 - Moderate. Obsessively dwells on guilt, wrongdoing, or hurting others by something they did or did not do, but can easily shift their focus to other things.

5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something; can shift focus to other things but only with great effort. Not delusional.

6 - Severe. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. Moderate absent-mindedness present.

7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on the delusion.

The inventors have determined that increased scores on the BPRS item "Guilt" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "Guilt" impair self-care, mother-child interaction, psychological health, and management.

Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, mother-child interaction, psychological well-being, and/or management.

In the study group that received the individualized dosing regimen, the total score for the BPRS item "guilt" was 34 at baseline for all eight patients. After 3 hours, the score dropped to 14, which corresponds to an improvement of 20 points or 59%. On the first day after treatment, the score dropped to 11, which corresponds to an improvement of 23 points or 68%. On the seventh day after treatment, the score dropped to 10, which corresponds to an improvement of 24 points or 71%.

In the 12 mg group, the total score of the BPRS item "guilt" for all 4 patients was 18 at baseline. After 3 hours, the score dropped to 9, which corresponds to an improvement of 9 points or 50%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%.

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

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

Improvement in guilt feelings, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in guilt feelings (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in guilt feelings (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of guilt achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total BPRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

As guilt may also influence other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvements in the "guilt" item of the BPRS will additionally contribute to the overall improvement in maternal functioning.

The BPRS item "Anxiety" relates to reported worry, nervousness, fear, panic, or concern. Possible scores are:

1- No anxiety.

2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

3 - Mild. Frequent worrying but able to easily shift attention to other things.

4-Moderate. Worried most of the time and unable to easily redirect attention, but functioning is not impaired; or anxious occasionally with autonomic symptoms, but functioning is not impaired.

5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms or some areas of functioning are disrupted by anxiety or worry.

6 - Severe. Anxiety is daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

The inventors have determined that increased scores on the BPRS item "Anxiety" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). Increased scores on the BPRS item "Anxiety" can impair psychological health, social support and management.

Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, social support, and/or management.

In the study group that received the individualized dosing regimen, the total score for the BPRS item "Anxiety" for all eight patients was 37 at baseline. After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points or 54%.

In the 12 mg group, the total score of the BPRS item "anxiety" for all 4 patients was 25 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 14 points or 56%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%.

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

The reduction or elimination of anxiety is reflected in at least an improvement in the score of the BPRS item Anxiety at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and/or on day 28.

Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in anxiety (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in anxiety (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of anxiety achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total BPRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as 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.

As anxiety may also influence other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvements in the "anxiety" item of the BPRS will additionally contribute to the overall improvement in maternal functioning.

The BPRS item "Tense" is related to observable physical and motor manifestations of nervousness, "nervousness," and agitation. Possible scores are

1- No tension.

2 - Very mild. More irritable than most people but within normal limits. Some brief signs of nervousness, such as picking at nails, rocking feet, excessive scratching of scalp, or finger tapping.

3 - Mild. Same as "2", but nervous signs are more frequent or exaggerated.

4-Moderate. Signs of motor tension are numerous and frequent, sometimes one or more signs occur simultaneously, e.g., shaking of the feet with twisting of the hands. Sometimes signs of tension are absent.

5 - Moderate to severe. Many and frequent signs of motor strain, often with one or more signs present at the same time. Still, in rare cases, no signs of strain are present.

6 - Severe. Same as "5", but signs of tension are persistent.

7 - Extreme. Multiple motor signs of nervousness persist, such as constant pacing and hand twisting.

The inventors have determined that increased scores on the BPRS item "strain" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "strain" impair mother-child interaction and psychological health.

Conversely, improvements on this BPRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains mother-child interaction and/or psychological well-being.

In the study group that received the individualized dosing regimen, the total score for the BPRS item "Tense" was 16 at baseline for all eight patients. After 3 hours, the score dropped to 11, which corresponds to an improvement of 5 points or 31%. On the first day after treatment, the score dropped to 11, which corresponds to an improvement of 5 points or 31%. On the seventh day after treatment, the score dropped to 10, which corresponds to an improvement of 6 points or 38%.

In the 12 mg group, the total score for the BPRS item "Tense" was 14 at baseline for all 4 patients. After 3 hours, the score dropped to 9, which corresponds to an improvement of 5 points or 36%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%.

The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve reduction or elimination of stress.

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

Improvement in stress, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

Improvement in stress (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in tension (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The inventors also concluded that the reduction or elimination of stress achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total BPRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as 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.

As stress may also influence other aspects of psychiatric or neurological disorders, the inventors conclude that the observed improvements in the "stress" item of the BPRS will additionally contribute to the overall improvement in maternal functioning.

Improvement in one or more aspects of the mental or nervous system disorder will also result in overall improvement.Preferably, treatment results in remission.

Relief of depressive symptoms can be reflected by a MADRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; occurs on the 1st day, e.g., 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Further, alternatively or additionally, relief from depressive symptoms can be reflected by a HAM-D score equal to or less than 7 and occurring no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; occurring on the 1st day, e.g., 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.

As can be seen from the above, treatment of patients with mental or nervous system disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof will not only result in a reduction in MADRS scores (including, in particular, the sub-scores as detailed above), but will also result in improvements in the BIMF scale domains. As discussed in the Examples section below, clinical data confirms a reduction in MADRS scores and improvements in maternal function.

The improvement of maternal function includes the improvement of self-care function domain.For example, the improvement of MADRS project laziness and/or sleep reduction can lead to the increase of BIMF scale score reflecting self-care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 10%, more preferably at least 20%.

The improvement of maternal function includes the improvement of infant care function area.For example, the improvement of MADRS project lazy and/or difficulty concentrating can lead to the increase of BIMF scale score reflecting infant care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 15%, more preferably at least 25%.

The improvement of maternal function includes the improvement of mother-child interaction functional domain. For example, the improvement of MADRS project sensory loss and inner tension can lead to the increase of BIMF scale score reflecting mother-child interaction. The improvement of the cumulative score of BIMF scale project reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

The improvement of maternal function includes the improvement of mental health function field.For example, the improvement of MADRS project laziness, pessimistic thoughts, sensory loss, inner tension and/or sleep reduction can lead to the increase of BIMF scale score reflecting mental health.The improvement of the cumulative score of BIMF scale project reflecting mental health is preferably at least 25%, more preferably at least 35%.

The improvement of maternal function includes the improvement of social support function domain. For example, the improvement of pessimistic thoughts of MADRS project will lead to the increase of BIMF scale score reflecting social support. The improvement of the cumulative score of BIMF scale project reflecting social support is preferably at least 10%, more preferably at least 20%.

The improvement of maternal function includes the improvement of management function area.For example, the improvement of MADRS project laziness, pessimistic thoughts and/or difficulty in concentrating attention can lead to the increase of BIMF scale score reflecting management.The improvement of the cumulative score of BIMF scale project reflecting management is preferably at least 20%, more preferably at least 30%.

The improvement of maternal function includes the improvement of the domain of regulation function. For example, the improvement of MADRS item laziness can lead to an increase in the BIMF scale score reflecting regulation. The improvement of the cumulative score of the BIMF scale items reflecting regulation is preferably at least 5%, more preferably at least 15%.

Improvement in maternal functioning relates to one or more, in particular two or more, domains of functioning selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

The BIMF total score is improved by 10% or more, preferably by 20% or more.

Breastfeeding

As noted above, for many medications, a breastfeeding patient may be faced with a situation where a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from treatment.

If a decision is made to stop breastfeeding in order to receive treatment, this decision will have a negative impact on maternal functioning, particularly impairing the domains of mother-child interaction and psychological well-being.

The present invention also addresses the need for treating psychiatric or neurological disorders in breastfeeding mothers without nearly total interruption of breastfeeding.

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

The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT to determine the time point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt that breastfeeding can be initiated without exposing the breastfed infant to any associated risks.

Absorption and distribution of inhaled 5-MeO-DMT are rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

The plasma protein binding rate is low (13-23%).

Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

Metabolites of 5-MeO-DMT that may occur in humans were identified to assess the potential relevance of such metabolites. In an in vitro metabolic characterization 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:

Table 1

Compound Relative proportion Bufotenine (5-OH-DMT) 5% 5-MeO-DMT 7% 5-MeO-DMT-N-oxide 1% 5-Methoxyindole-3-ethanol (5-methoxytryptol) 25% 5-Methoxyindoleacetic acid (5-MIAA) 61%

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

The metabolites listed in the table above are formed via three different pathways.

The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed by oxidative deamination. This involves enzymatic removal of the N-methyl group and oxidation to form acetaldehyde:

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

No secondary amines, primary amines, or aldehydes were identified, indicating that they were not present in significant concentrations at any time.

The aldehyde intermediate metabolite undergoes two independent biotransformations in human hepatocytes. The aldehyde intermediate metabolite is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol.

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

Because the major pathway of 5-MeO-DMT metabolism rapidly produces metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptol with human hepatocytes indicated a high metabolic turnover rate, with the compound completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptol was 16.2 μl/min/million cells (half-life 142 minutes).

Therefore, the plasma concentration of 5-methoxytryptol (to the extent that it is formed) will drop rapidly and reach endogenous levels.

5-MIAA is a weak acid that will be present in plasma in an ionized form, thereby reducing the possibility of the compound entering breast milk.

Incubation of 5-MIAA with human hepatocytes indicated a low metabolic turnover rate, with the remaining 5-MIAA concentration being 75-82% after 72 h. 5-MIAA is considered to be the final metabolite of 5-MeO-DMT.

5-MIAA exhibits a relatively low plasma binding rate (mean unbound fraction (Fu); see Examples section) of about 50%. After renal clearance, 5-MIAA remains in the circulation. Given the standard glomerular filtration rate of 90-120 ml/min, this means that within approximately 1-2 hours, all traces of 5-MIAA are removed from the circulation and excreted in the urine (depending on the patient's size and taking into account the increase in blood volume that occurs during pregnancy).

Therefore, the plasma concentration of 5-MIAA will also decrease rapidly.

Together with the rapid clearance of 5-MeO-DMT (<1 h), this supports the notion that the administered therapy and all associated metabolites are cleared from the circulation within approximately 2 h.

Another identified metabolite, bufotoxin, is the result of O-demethylation catalyzed by CYP2D6. The resulting metabolite is then glucuronidated by UGT:

As part of the pharmacokinetic studies, it was determined that bufotoxin was virtually undetectable in human serum. In any case, bufotoxin was undetectable 15 minutes after administration of 5-MeO-DMT.

Toad serotonin glucuronide cannot bind to the receptor and does not play any role. In addition, the concentration of toad serotonin glucuronide is so low that it cannot be detected in the hepatocyte assay. Toad serotonin glucuronide is further converted to 5-hydroxyindoleacetic acid:

5-Hydroxyindoleacetic acid is an endogenous substance which is present, for example, in the metabolism of melatonin and serotonin (cf. above).

Since the O-demethylation pathway of 5-MeO-DMT produces the major metabolite bufotoxin, which is rapidly cleared from plasma and further metabolism produces compounds that are only present at very low concentrations and ultimately produce metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions on breastfeeding.

The third metabolic pathway involves N-oxidation:

In computer simulations of the metabolites formed, 5-MeO-DMT-N-oxide was considered to be non-genotoxic, which is consistent with the negative in vitro genotoxicity assessment of the parent molecule. As confirmed by observations in rats, the compound is soluble in water and can be rapidly excreted (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 5-MeO-DMT metabolic pathway involving N-oxidation plays only a minor role and results in a low proportion of metabolites without obvious toxicity, the metabolites are rapidly excreted, so the inventors determined that the N-oxidation of 5-MeO-DMT does not involve metabolites that require restrictions on breastfeeding.

Based on the above, the inventors determined that breastfeeding can be resumed shortly after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Therefore, if the patient is a breastfeeding mother, she is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Specifically, she is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Preferably, breastfeeding must be interrupted for only 6 hours, more preferably, for only 3 hours, and most preferably, for only 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

This brief interruption and the possibility of resuming breastfeeding soon after treatment contributes to the success of the treatment and, in particular, to the functioning of the mother and the health and development of the infant.

Treatment of mental or nervous system disorders

Disorders characterized by depressive episodes

Several disorders are characterized by depressive episodes.

A depressive episode is a period of depressed mood and/or loss of interest in most activities.

For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms within the same 2-week period that represent a change from previous functioning; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

Disorders characterized by depressive episodes involve one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

For example, severity and treatment success can be assessed 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 associated with processing, regulating, emotional memory; cognitive processes related to rumination; impaired concentration and physiological arousal.

Treatment of a patient suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in an improvement in the disorder characterized by depressive episodes.

Improvement in disorders characterized by a depressive episode (reflected by a decrease in CGI-S scores) is observed at 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; on day 7; on day 14; and/or on day 28.

The patient's improvement in the disorder characterized by a depressive episode (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by a depressive episode (reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in disorders characterized by a depressive episode (reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours later; 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.

The patient's improvement in a disorder characterized by a depressive episode (reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in a disorder characterized by a depressive episode (reflected by a decrease in the MADRS score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in disorders characterized by a depressive episode (reflected by a decrease in HAM-D score) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The patient's improvement in a disorder characterized by a depressive episode (as reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in a disorder characterized by a depressive episode (as reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in a patient suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from a disorder characterized by depressive episodes occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 that causes persistent feelings of sadness and loss of interest. MDD 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 higher, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or higher. It is further considered that patients may have severe major depressive disorder, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or higher.

Patients suffering from MDD may suffer from a treatment-resistant (TRD) form of the disorder.

MDD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with MDD, functional connectivity disturbances and modulations were observed within and/or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

Treatment of patients suffering from MDD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of MDD.

Improvement in MDD (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in MDD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in MDD (reflected by a decrease in MADRS score) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The patient's improvement in MDD (reflected by a decrease in MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (reflected by a decrease in MADRS score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in MDD (reflected by a decrease in HAM-D score) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The patient's improvement in MDD (reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from MDD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from MDD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 called dysthymia, is a chronic form of depression. It is diagnosed if depression is present most of the time, most of the days, for at least 2 years. Any symptom-free period is less than 2 months.

To be depressed, two or more of the following symptoms must be present: 1. Hopelessness 2. Lack of energy or fatigue 3. Low self-esteem 4. Decreased sleep (insomnia) or increased sleep (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 involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with persistent depressive disorder, altered functional connectivity was observed within and/or between several brain regions associated with processing, regulation, emotional memory; cognitive processes associated with rumination; impaired concentration and physiological arousal. Functional connectivity impairment was observed within and/or between the DMN, salience network, executive control network and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S scores) is observed at 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; on day 7; on day 14; and/or on day 28.

The improvement of the patient's persistent depressive disorder (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of the persistent depressive disorder (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 score) is observed on day 1, e.g., about 24 hours after; 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.

The improvement of the patient's persistent depressive disorder (reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of the persistent depressive disorder (reflected by a decrease in the MADRS score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until 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 HAM-D score) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The patient's improvement in persistent depressive disorder (reflected by a decrease in HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in persistent depressive disorder (reflected by a decrease in HAM-D score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from persistent depressive disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from persistent depressive disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Seasonal Affective Disorder

Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms typically starting in the fall and easing in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

Seasonal affective disorder involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

In patients with seasonal affective disorder, altered functional connectivity was observed within and/or between several brain regions associated with processing, regulating, emotional memory; cognitive processes associated with rumination; impaired concentration and physiological arousal. Functional connectivity impairment was observed within and/or between the DMN, salience network, executive control network and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S scores) is observed at 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; on day 7; on day 14; and/or on day 28.

The improvement of the patient's seasonal affective disorder (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of seasonal affective disorder (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in seasonal affective disorder (reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours after; 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.

The improvement of the patient's seasonal affective disorder (reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of seasonal affective disorder (reflected by a decrease in the MADRS score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in seasonal affective disorder (reflected by a decrease in HAM-D score) is observed on day 1, e.g., about 24 hours after; 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.

The improvement of the patient's seasonal affective disorder (reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of seasonal affective disorder (reflected by a decrease in the HAM-D score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until 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 seasonal affective disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from seasonal affective disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 dramatic mood swings, including periods of low moods (major depressive episodes) and high moods (manic or hypomanic episodes). BD is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

Patients suffering from BD may suffer from a treatment-resistant form of the disorder.

If at least one manic episode occurs (with or without a depressive episode), BD is classified as bipolar disorder type I. If at least one hypomanic episode (but not a full manic episode) and one major depressive episode occur, BD is classified as bipolar disorder type II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

Patients with BD, whether diagnosed with bipolar II or bipolar I, are particularly susceptible to having a current major depressive episode.

The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score equal to or greater than 19, such as greater than or equal to 24, in particular greater than or equal to 37.

Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

BD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal, and negative thinking.

For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAM-D), or the Bipolar Depression Rating Scale (BDRS).

BDRS is designed to measure the severity of depressive symptoms in bipolar depression. BDRS has been validated by trained assessors and can be used clinically. Based on clinical interviews, BDRS projects assess the severity of depression and/or mixed symptoms that patients show in the current and past few days. If the current symptoms are inconsistent with the symptoms of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the highest possible score is 60. The higher the score, the higher the severity.

The problems addressed are: depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

Each of these aspects was assessed and scored 0, 1, 2, or 3.

Patients with BD display characteristic abnormalities in the intrinsic organization and interconnectivity of resting-state networks. Resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity of specific regions within and/or between the default mode network, salience network, and central executive network compared to healthy controls. In particular, altered functional connectivity within the default mode network has been observed in patients with sleep disturbances.

Treatment of patients suffering from BD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BD.

Improvement in BD (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in BD (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BD (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD (reflected by a decrease in MADRS score) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The patient's improvement in BD (reflected by a decrease in MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BD (reflected by a decrease in MADRS score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD (reflected by a decrease in HAM-D score) is observed on day 1, e.g., about 24 hours after; 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.

The patient's improvement in BD (reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BD (reflected by a decrease in the HAM-D score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in BD (reflected by a decrease in BDRS score) is observed on day 1, e.g., about 24 hours after; 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.

The patient's improvement in BD (reflected by a decrease in BDRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BD (reflected by a decrease in BDRS score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 BD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from BD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Anxiety disorders

Anxiety disorders are mental health conditions. Symptoms include feelings of nervousness, panic, and fear, as well as sweating and a racing heartbeat. Anxiety involves a complex system of cognitive, emotional, physiological, and behavioral responses related to preparation for an anticipated event or situation that is perceived as a threat.

Anxiety disorders also involve one or more of 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item “anxiety”.

Additionally, anxiety disorders are associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Anxiety disorders are studied by functional magnetic resonance imaging. Generally speaking, all anxiety disorders show abnormalities in the default mode network (DMN). Other networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). Relative to the DMN, the resting state balance within and/or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

Treatment of patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in a patient suffering from an anxiety disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from an anxiety disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from anxiety disorders (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from anxiety disorders (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in a patient suffering from such an anxiety disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in a patient suffering from such an anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in a patient suffering from such an anxiety disorder (including treatment-resistant forms of the disorder) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from an anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from an anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Mood Item (Item 1) of the HAM-A) in a patient suffering from an anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than 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 Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from anxiety disorders (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from anxiety disorders (including treatment-resistant forms of said disorders) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from anxiety disorders (including treatment-resistant forms of said disorders) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The above applies generally to anxiety disorders, including the specific conditions discussed in detail below, as well as anxiety disorders due to a medical condition, which occur when the medical condition causes extreme fear, anxiety, or panic; other specified anxiety disorders, which may be diagnosed if a patient meets most but not all of the criteria for an anxiety disorder; and unspecified anxiety disorders, which are usually diagnosed if a patient experiences anxiety or panic but lacks information to fully diagnose another anxiety disorder.

Improvement in maternal functioning in patients suffering from an anxiety disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from anxiety disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 leaving home and/or being separated from people to whom the patient has a strong emotional attachment.

Separation situations can cause patients great distress, and they may have difficulty attending school or work because of the separation. People with separation anxiety disorder may also feel excessive anxiety about unwelcome events that happen to important people in their lives, such as family members.

Separation anxiety disorder also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from separation anxiety disorder may suffer from 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

Additionally, separation anxiety disorder is associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Separation anxiety disorder is studied by functional magnetic resonance imaging. Generally speaking, all anxiety disorders show abnormalities in the default mode network (DMN). Other networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). Relative to the DMN, the resting state balance within and/or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

Treatment of patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in a patient suffering from separation anxiety disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from separation anxiety disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in a patient suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in a patient suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on the 1st day, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in scores on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety (reflected by a decrease in the score on the Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected by a decrease in the score on the Anxiety Mood Item (Item 1) of the HAM-A) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 dissociative disorders is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected in improvement in BIMF total score) in patients suffering from dissociative disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Agoraphobia is the fear of situations or places that may cause feelings of panic, entrapment, helplessness, or embarrassment.

People with agoraphobia may have difficulty leaving the house. The thought of leaving the house may cause considerable anxiety, even leading to avoidance. Fear of crowds, travel, elevators, movie theaters, shopping malls, etc. may cause significant challenges.

People with agoraphobia may also experience recurring panic attacks.

Agoraphobia also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from agoraphobia may suffer from 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

Additionally, agoraphobia is associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Functional magnetic resonance imaging of individuals with agoraphobia reveals alterations in functional connectivity within and/or between resting-state networks involved in anxiety.

Treatment of patients suffering from agoraphobia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in a patient suffering from agoraphobia is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from agoraphobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, compared to the corresponding scores before treatment.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in patients suffering from such agoraphobia (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such agoraphobia (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such agoraphobia (including treatment-resistant forms of the disorder) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) occurs no later than 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 Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from agoraphobia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 agoraphobia is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from agoraphobia occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 uncontrollable worry about a variety of situations and problems. People with GAD may anticipate disasters and may worry excessively about money, health, family, work, or other issues.

GAD is diagnosed when an individual experiences persistent worry about everyday challenges that is out of proportion to the perceived threat. People with GAD typically experience excessive fear that lasts for months to years.

GAD can interfere with social, occupational, or other important areas of functioning.

GAD also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from GAD may suffer from 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item “anxiety”.

Additionally, GAD is associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

GAD patients also show altered functional connectivity, particularly within the default mode network.

Treatment of patients suffering from GAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in patients suffering from GAD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in patients suffering from GAD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in patients suffering from GAD, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A score of at least 50% compared to the corresponding score before treatment at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from GAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from GAD (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in patients suffering from such GAD (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such GAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such GAD (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in scores on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from GAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from GAD, including treatment-resistant forms of the disorder, occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from GAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from GAD, including treatment-resistant forms of the disorder, occurs no later than 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 Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from GAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from GAD (including treatment-resistant forms of the disorder) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from GAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from GAD, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from GAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 GAD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from GAD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 may cause impairment in school, work, or relationships.

SAD also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from SAD may suffer from 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

Additionally, SAD is associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

In SAD patients, altered functional connectivity within and/or between resting-state networks, such as the default mode network and the salience network, is observed.

Treatment of patients suffering from SAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in patients suffering from SAD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from SAD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in a patient suffering from SAD, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A score of at least 50% compared to the corresponding score before treatment at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from SAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from SAD (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in patients suffering from such SAD (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such SAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such SAD (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in scores on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from SAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from SAD (including treatment-resistant forms of the disorder) occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from SAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from SAD (including treatment-resistant forms of the disorder) occurs no later than 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 Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from SAD (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from SAD (including treatment-resistant forms of the disorder) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from SAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from SAD, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from SAD (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 SAD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from SAD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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, intense fear or discomfort that peaks within a few minutes.

Panic attacks are characterized by multiple somatic symptoms of anxiety, including sweating, shaking, trembling, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

In addition, the disorder can often be characterized by anxiety about future panic attacks. The patient may become extremely concerned about the possibility of another attack.

Panic disorder also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from panic disorder may suffer from 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

Additionally, panic disorder is associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Patients with panic disorder show altered functional connectivity within and/or between the default mode network and the sensorimotor network.

Treatment of patients suffering from panic disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in patients suffering from panic disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from panic disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in patients suffering from panic disorder (including treatment-resistant forms of the disorder) is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from panic disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from panic disorder (including treatment-resistant forms of the disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in a patient suffering from such panic disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such panic disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such panic disorder (including treatment-resistant forms of the disorder) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in scores on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from panic disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from panic disorder (including treatment-resistant forms of the disorder) occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from panic disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from panic disorder (including treatment-resistant forms of the disorder) occurs no later than 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 Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from panic disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from panic disorder (including treatment-resistant forms of the disorder) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from panic disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from panic disorder, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from panic disorder (including treatment-resistant forms of the disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from panic disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from panic disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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. People with phobias experience extreme anxiety when anticipating or coming into contact with the phobic stimulus. There are phobias of animals (spiders, snakes, dogs), natural environments (tornadoes, heights, water, fire), blood injections (needles, medical procedures), situations (flying in airplanes, enclosed spaces), and others (those that don't fit into the previous categories).

Phobias usually cause a rapid onset of fear that often persists for more than six months. People will go to great lengths to avoid the feared stimulus. The fear and avoidance may cause significant distress and/or impairment in occupational, academic, or social functioning.

Phobias also involve one or more of sleep disturbances, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

Patients suffering from phobias may suffer from a treatment-resistant form 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 psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item "anxiety".

Additionally, phobias are associated with suicidal ideation.

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 over-responsive to phobia-related stimuli. For example, functional neuroimaging studies have found that the dorsal part of the anterior cingulate cortex (dACC), which is part of the salience network, is over-responsive to phobia-related stimuli or the anticipation of such stimuli.

Treatment of patients suffering from phobias, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in a patient suffering from a phobia is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from a phobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in patients suffering from phobias, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from phobias, including treatment-resistant forms of the disorder, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from phobias, including treatment-resistant forms of the disorder, preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in patients suffering from such phobias, including treatment-resistant forms of the disorder, is reflected in a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such phobias, including treatment-resistant forms of the disorder, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in patients suffering from such phobias, including treatment-resistant forms of the disorder, preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from phobias (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from phobias, including treatment-resistant forms of the disorder, occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from a phobia (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Anxiety Item (Item 1) of the HAM-A) in patients suffering from phobias, including treatment-resistant forms of the disorder, occurs no later than 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 Anxiety Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from phobias (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from phobias (including treatment-resistant forms of said disorders) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from phobias, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from phobias, including treatment-resistant forms of the disorder, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from phobias, including treatment-resistant forms of the disorder, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from phobia is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected in improvement in BIMF total score) in patients suffering from phobia occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Substance-induced anxiety disorder is an anxiety disorder in which anxiety or panic attacks occur after alcohol use, drug abuse, or medication use, or after exposure to toxins. Substance-induced anxiety disorders cause significant panic or anxiety symptoms and may occur during periods of intoxication or withdrawal from substance or medication use.

The disorder causes significant distress and/or impairment in social, occupational, or other important areas of functioning.

While taking the substance or medication or within a short period of time after taking it, individuals with substance/medication-induced anxiety disorders may feel nervous and worried, experience symptoms of negative thinking, may have trouble concentrating or remembering things, may have fears of losing control or becoming insane or dying, may lose weight due to gastrointestinal problems, may experience chills, hot flashes, sweating, shivering, numbness or a racing heartbeat, trouble breathing, difficulty swallowing, or chest pain.

Substance/medication-induced anxiety disorders also involve one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal, and negative thinking.

The severity of substance/medication-induced anxiety disorders can be assessed using the Beck Anxiety Inventory (BAI). Other measures include the Hamilton Anxiety Rating Scale (HAM-A); the psychiatric anxiety subscale of the HAM-A (sum of items 1-6 and 14); the anxious mood item of the HAM-A (item 1); and the Brief Psychiatric Rating Scale (BPRS) item “anxiety.”

Substance/medication-induced anxiety disorders have also been associated with suicidal ideation.

Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Functional magnetic resonance imaging of individuals with substance/medication-induced anxiety disorders reveals alterations in functional connectivity within and/or between resting-state networks involved in anxiety.

Treatment of patients suffering from substance/medication induced anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

A reduction or elimination of anxiety in a patient suffering from a substance/medication induced anxiety disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety in a patient suffering from a substance/medication induced anxiety disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A clinical response in a patient suffering from a substance/medication induced anxiety disorder, including treatment-resistant forms of the disorder, is reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The clinical response (reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) in patients suffering from substance/drug induced anxiety disorders (including treatment-resistant forms of said disorders) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response (reflected by a decrease of at least 50% in the HAM-A score) in patients suffering from substance/drug induced anxiety disorders (including treatment-resistant forms of said disorders) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Relief of anxiety in a patient suffering from such substance/medication induced anxiety disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

Relief of anxiety (as reflected by a HAM-A score of 7 or less) in a patient suffering from such substance/drug induced anxiety disorder (including treatment resistant forms of said disorder) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety (as reflected by a HAM-A score of 7 or less) in a patient suffering from such substance/drug induced anxiety disorder (including treatment resistant forms of said disorder) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Psychotic Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) is observed in patients suffering from substance/medication induced anxiety disorders (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) in patients suffering from substance/medication induced anxiety disorders, including treatment-resistant forms of said disorders, occurs no later than 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 Psychiatric Anxiety subscale (sum of items 1-6 and 14) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the Anxiety Mood item (Item 1) of the HAM-A) is observed in patients suffering from a substance/medication induced anxiety disorder (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of anxiety (reflected by a decrease in the score on the Anxiety Mood Item (Item 1) of the HAM-A) in patients suffering from substance/medication induced anxiety disorders (including treatment resistant forms of said disorders) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected by a decrease in the score on the Anxiety Mood Item (Item 1) of the HAM-A) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A reduction or elimination of anxiety (as reflected by a decrease in the score on the BPRS item "Anxiety") is observed in patients suffering from substance/medication induced anxiety disorders (including treatment-resistant forms of the disorder) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and/or at 28 days 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 of the BPRS item "Anxiety") in patients suffering from substance/medication-induced anxiety disorders (including treatment-resistant forms of said disorders) occurs no later than 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 of the BPRS item "Anxiety") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Treatment of patients suffering from substance/medication induced anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

A reduction or elimination of suicidal ideation in patients suffering from substance/medication induced anxiety disorders, including treatment-resistant forms of the disorders, is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., 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 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

Reduction or elimination of suicidal ideation in patients suffering from substance/medication induced anxiety disorders (including treatment-resistant forms of said disorders) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of suicidal ideation preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 substance/medication induced anxiety disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from substance/medication induced anxiety disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 that is diagnosed when a person becomes so preoccupied with physical symptoms, such as pain, weakness, or shortness of breath, that it causes significant distress and/or problems functioning and/or disrupts their daily life. Feelings and behaviors associated with the disorder are excessive or disproportionate.

Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorder, the impairment is significant, and when it persists, the disorder may lead to disability.

Somatic symptom disorder involves one or more of sleep disturbance, cognitive dysfunction, and anxiety.

Brain functional connectivity analysis revealed alterations within and/or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Alterations were found within and/or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor networks. Somatic symptom disorder may be associated with alterations in sensory discrimination processing of somatic symptoms, which is affected by affective 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 disorder (reflected by a decrease in CGI-S score) is observed at 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; on day 7; on day 14; and/or on day 28.

The patient's improvement in somatic symptom disorder (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in somatic symptom disorder (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 somatic symptom disorder is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from somatic symptom disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Obsessive-compulsive disorder and related disorders

Obsessive compulsive disorder (OCD) is a mental illness that causes repetitive unwanted thoughts or feelings (obsessions) or the urge to do something over and over again (compulsions). People may have both obsessions and compulsions.

Patients suffering from OCD may suffer from a treatment-resistant form of the disorder.

OCD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Neuroimaging studies using functional magnetic resonance imaging on patients with OCD have shown altered functional connectivity within and/or between the frontoparietal, salience, and default mode networks. Altered functional connectivity of the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in OCD (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in OCD (reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 OCD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients suffering from OCD (as reflected by improvement in BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

People with body dysmorphic disorder (BDD) falsely perceive imperfections in their appearance that disrupt their ability to live daily lives and are accompanied by disturbing thoughts, ritualistic behaviors, and emotional distress.

Patients suffering from BDD may suffer from a treatment-resistant form of the disorder.

BDD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Functional magnetic resonance imaging of patients with BDD revealed alterations within and/or between certain brain regions located within the default mode network, dorsal attention network, and salience network. Altered functional connectivity of the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

Treatment of patients suffering from 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 score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours later; at day 7; at day 14; and/or at day 28.

The patient's improvement in BDD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BDD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 BDD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from BDD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 based on a terrifying event that the patient has experienced or witnessed. Symptoms can include flashbacks, nightmares, and severe anxiety and uncontrollable thoughts about the event.

Patients suffering from PTSD may suffer from a treatment-resistant form of the disorder.

PTSD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state functional magnetic resonance imaging analyses of patients with PTSD revealed alterations within and/or between regions within the default mode network and the salience network.

Treatment of patients suffering from PTSD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvements in PTSD.

Improvements in PTSD (reflected by a decrease in CGI-S scores) are observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in PTSD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in PTSD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from PTSD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients suffering from PTSD (as reflected by improvement in BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 called persistent pain, is long-term pain that persists beyond the normal recovery period (for example, after an injury or surgery) despite medication or treatment. Patients may also develop chronic pain without any obvious cause, such as a history of injury or surgery.

Chronic pain is associated with one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Chronic pain patients display brain alterations regarding both function and structure. These changes are associated with the persistence of pain, long after the initial noxious input has ceased. Resting-state functional magnetic resonance imaging reveals alterations in distinct regions within and/or between the default mode network, somatomotor/sensorimotor networks, and salience networks.

Treatment of patients suffering from chronic pain, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement in chronic pain.

Improvement in chronic pain (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28.

The improvement of the patient's chronic pain (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of chronic pain (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 chronic pain is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected by improvement in BIMF total score) in patients suffering from chronic pain occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain throughout the body or in multiple sites, and associated fatigue, sleep disturbances, memory and mood problems. Sufferers may also experience muscle and joint stiffness, tenderness, numbness or tingling in the arms and legs, difficulty concentrating, unclear thinking and memory loss (sometimes called "fibro fog"), increased sensitivity to light, noise, smells and temperature, or digestive problems, such as bloating or constipation.

Studies have shown that people with fibromyalgia have a heightened sensitivity to pain, so they feel pain when others don’t.

Fibromyalgia involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Brain imaging studies and other research have found evidence that people with fibromyalgia have altered signaling in the neural pathways that transmit and receive pain. These changes may also contribute to the fatigue, sleep disturbances and cognitive problems that many people with the disorder experience.

Resting-state functional magnetic resonance imaging in patients with fibromyalgia revealed 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 suffering from fibromyalgia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the fibromyalgia.

Improvement in fibromyalgia (reflected by a decrease in CGI-S score) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in fibromyalgia (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in fibromyalgia (reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 fibromyalgia is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from fibromyalgia occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

A migraine is a type of headache that causes severe throbbing pain or a pulsating sensation, usually on one side of the head. Migraines are often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last from a few hours to a few days, and the pain can be so severe that it interferes with daily activities.

In some patients, a symptom called an aura occurs before or at the same time as the headache. This symptom can 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 an arm or leg, and difficulty speaking.

Migraines are associated with one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Headache disorders were associated with atypical functional connectivity in regions involved in pain processing and within and/or between multiple core resting-state networks, including the salience network and the default mode network.

In patients with migraine, resting-state network analyses revealed differences from healthy controls. Studies during migraine attacks revealed significant abnormalities in networks involved in mediating cognitive, attentional, somatosensory, and affective components of pain.

Treatment of patients suffering from migraine, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the migraine.

Improvement in migraine (reflected by a decrease in CGI-S score) is observed at 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; on day 7; on day 14; and/or on day 28.

The patient's improvement in migraine (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in migraine (reflected by a decrease in CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 migraine is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from migraine occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Mental and behavioral disorders due to psychoactive substance use

Sleep disturbances occur in patients with certain psychiatric and behavioral disorders caused by the use of psychoactive substances.

Substance use disorder (SUD) is a mental disorder that affects a person's behavior, causing a person to lose control of their use of substances (such as legal or illegal drugs, alcohol, or medications). Symptoms can range from moderate to severe, and addiction is the most severe form of SUD.

Substance use disorders involve one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

Resting-state functional connectivity (rsFC) was found to be altered not only in patients with sleep disorders but also in patients with substance use disorders. Specifically, cognitive control deficits were associated with altered connectivity within and/or between resting-state networks such as the default mode network, salience network, central executive network, limbic network, and reward network.

Treatment of patients suffering from 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 substance use disorder (reflected by a decrease in CGI-S score) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in substance use disorder (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in substance use disorder (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in a patient suffering from a substance use disorder is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected by improvement in BIMF total score) in patients suffering from substance use disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Psychotic Disorders

Psychotic disorders are severe mental disorders that cause abnormalities in thinking and perception. Psychotic disorders are characterized by significant impairment of reality testing ability and behavioral changes, manifested by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking (usually manifested as disorganized speech), severely disorganized behavior, and experiences of passivity and control, and negative symptoms such as blunted or apathetic affect, loss of will, and psychomotor disturbances.

Patients suffering from a psychotic disorder may suffer from a treatment-resistant form of the disorder.

Psychotic disorders involve one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

Imaging the brains of patients with psychotic disorders using functional magnetic resonance imaging of resting-state networks revealed significant alterations in different regions within and/or between the central executive, default mode, and salience networks. Alterations in resting-state networks could be identified even in a patient group at risk for psychosis.

Treatment of patients suffering from a psychotic disorder, 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 disorders (reflected by a decrease in CGI-S scores) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in psychotic disorder (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in psychotic disorder (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in a patient suffering from a psychotic disorder is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from psychotic disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 disorder characterized by disturbances in multiple mental patterns, including thinking, perception, self-experience, cognition, volition, emotion, and behavior. Psychomotor disturbances, including catatonia, may occur.

Patients suffering from schizophrenia may suffer from a treatment-resistant form of the disorder.

Schizophrenia involves one or more of sleep disturbances, cognitive dysfunction, anxiety, social/emotional withdrawal, negative thinking, and psychomotor retardation.

Abnormalities in resting-state functional connectivity have been reported in individuals with schizophrenia, particularly within and/or between the default mode network, frontoparietal network, and salience network. Several studies have found associations between sleep disturbances and symptom severity in individuals at high risk for psychosis and those diagnosed with schizophrenia.

Treatment of patients suffering from schizophrenia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of schizophrenia.

Improvement in schizophrenia (reflected by a decrease in CGI-S score) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in schizophrenia (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in schizophrenia (reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from schizophrenia is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with schizophrenia (reflected in an improvement in the BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in an improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Eating disorders

Eating disorders are mental disorders 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 involve one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

In patients with eating disorders, results from functional network connectivity studies suggest disrupted resting-state connectivity within and/or between executive, default mode, and salience networks.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S scores) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in eating disorders (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in eating disorders (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 eating disorders is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from eating disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 disorder that affects a person's behavior. People with ADHD may seem restless, may have trouble paying attention, and may act impulsively.

ADHD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state network analysis of patients with ADHD revealed functional connectivity impairments between multiple brain resting-state networks, particularly within and/or between different regions of the default mode network, dorsal attention network, and salience network.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S score) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in ADHD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in ADHD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 ADHD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients suffering from ADHD (reflected in improvement in BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Personality disorders

Schizotypal personality disorder is a mental health condition characterized by persistent, extreme discomfort with relationships and social interactions. People with schizotypal personality disorder have abnormal thoughts, words, and behaviors that hinder their ability to form and maintain relationships.

Patients suffering from schizotypal personality disorder may suffer from a treatment-resistant form of the disorder.

Schizotypal personality disorder involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

In patients with schizotypal personality disorder, DMN functional connectivity, particularly that involved in cognitive or affective regulation, was altered. Neuroimaging analysis using fMRI further revealed alterations within and/or between the frontoparietal and dorsal attention networks.

Treatment of patients suffering from 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 (reflected by a decrease in CGI-S scores) is observed at 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; on day 7; on day 14; and/or on day 28.

The improvement of the patient's schizotypal personality disorder (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of schizotypal personality disorder (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal functioning in patients suffering from schizotypal personality disorder is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from schizotypal personality disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Persistent mood instability, impulsivity, identity disturbance, and interpersonal dysfunction are characteristic of borderline personality disorder (BPD).

Patients suffering from BPD may suffer from a treatment-resistant form of the disorder.

BPD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Patients with borderline personality disorder show abnormal connectivity patterns of resting-state networks. Analyzing the functional connectivity of the brain's resting-state networks using functional magnetic resonance imaging revealed alterations within and/or between various networks, such as, for example, the default mode network and the salience network.

Treatment of patients suffering from BPD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BPD.

Improvement in BPD (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in BPD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BPD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 BPD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients suffering from BPD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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. In addition, the disorder is characterized by a range of restricted, repetitive, and rigid patterns of behavior, interests, or activities that are clearly atypical or excessive for the individual's age and sociocultural background.

The disorder develops during development, but symptoms may not fully manifest until later in life. The impairment is severe enough to interfere with the individual's ability to function in personal, family, social, educational, occupational, or other areas.

ASD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, and social/emotional withdrawal.

ASD is a brain network connectivity disorder. Neuroimaging studies have shown that ASD is associated with abnormal responses in certain brain regions, significant changes in brain networks, including altered functional connectivity within and/or between the default mode network (DMN) and sensory processing networks, and disrupted neural synchronization between brain regions.

Treatment of patients suffering from ASD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the ASD.

Improvement in ASD (reflected by a decrease in CGI-S score) is observed 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; at day 7; at day 14; and/or at day 28.

The patient's improvement in ASD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in ASD (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 ASD is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients with ASD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Chronic fatigue syndrome

Fatigue describes a feeling of exhaustion, listlessness, and decreased energy. Fatigue occurs when a person's physical or mental resources become weak or depleted. Although it is considered normal to experience fatigue after a period of mental or physical exertion, fatigue can occur in the absence of such exertion and is a symptom of a health condition.

In addition, chronic fatigue that is exacerbated by activity is a cardinal symptom of chronic fatigue syndrome, a disorder in which severe fatigue is accompanied by neurocognitive, autonomic, and immune symptoms.

Various abnormalities in normal sleep patterns have been reported in patients with chronic fatigue syndrome that may serve as maintaining factors.

In the early stages of the disease, chronic fatigue syndrome patients often complain of excessive sleeping. Once the disease enters a more chronic stage, it often leads to a general decrease in sleep efficiency. Even if patients sleep for a long time, they often do not feel refreshed when they wake up.

Compensatory behaviors for a nonrestorative night's sleep may result in alterations in circadian rhythms. In addition, vivid dreams, periodic limb movements during sleep, and restless legs syndrome are frequently reported.

Chronic fatigue syndrome involves one or more of sleep disturbance, cognitive dysfunction, and anxiety.

Patients with chronic fatigue syndrome showed abnormal resting-state functional connectivity, which was significantly associated with the severity of their chronic fatigue. The network involved is 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 (reflected by a decrease in CGI-S score) is observed at 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; on day 7; on day 14; and/or on day 28.

The improvement of chronic fatigue syndrome in the patient (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of chronic fatigue syndrome (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 chronic fatigue syndrome is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from chronic fatigue syndrome occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Medical health conditions that lead to related psychiatric or neurological disorders

Traumatic brain injury patients

Traumatic brain injury (TBI) is damage to the brain caused by external force.

Traumatic brain injury is classified as either primary or secondary. Primary brain injury refers to structural damage that occurs at the time of impact from contact, acceleration-deceleration, and/or rotational forces. Secondary brain injury refers to damage caused by cellular processes that occur after the primary injury (i.e., hypoxia and/or increased intracranial pressure).

TBI results in one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting state functional connectivity analysis reveals changes in global functional connectivity within and/or between resting state networks such as the DMN, frontoparietal network, executive network, and sensorimotor network. For example, highly connected regions that can be found within the DMN are particularly susceptible to functional connectivity changes following traumatic brain injury.

Treatment of patients suffering from TBI, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the TBI.

Improvement in TBI (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in TBI (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in TBI (reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in a patient suffering from TBI is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected in improvement in BIMF total score) in patients suffering from TBI occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

HIV-infected patients

HIV disease is caused by infection with human immunodeficiency virus type 1 (HIV-1). Despite the use of combination antiretroviral therapy, HIV-infected patients can still develop symptoms of neurological disorders.

HIV causes one or more of sleep disturbance, cognitive dysfunction, anxiety, social/emotional withdrawal, and negative thinking.

Resting-state functional connectivity analysis of patients with neurocognitive impairment due to HIV infection showed impaired functional connectivity within and/or between certain regions of the default mode network, salience network, and executive network.

Treatment of patients suffering from HIV, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of HIV.

Improvement in HIV (reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and/or at day 28.

The patient's improvement in HIV (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in HIV (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until 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 HIV is reflected in at least an improvement in the BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function in patients with HIV (as reflected by improvement in BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Post-COVID patients

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Post-COVID illness (sometimes called “long COVID”) is a multisystem disorder that often includes severe symptoms following infection with SARS-CoV-2. It is an often debilitating condition that occurs in at least 10% of infections.

The World Health Organization (WHO) defines this disorder as a syndrome that appears within 3 months of infection, lasts for at least 2 months, may fluctuate, and cannot be explained by another diagnosis.

Post-COVID symptoms can include a variety of persistent health problems that can last for weeks, months, or years and sometimes lead to disability.

The most commonly reported typical symptoms of individuals suffering from post-COVID syndrome are such as fatigue, shortness of breath, and cognitive impairment, such as, for example, 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.

Even after surviving mild illness, patients with post-COVID syndrome often experience lingering symptoms such as anxiety. Post-COVID anxiety may be a direct result of SARS-CoV-2 infection or may result from hospitalization (particularly in an intensive care unit) associated with acute SARS-CoV-2 infection.

Individuals experiencing COVID-19 induced anxiety often worry about health and recovery, job loss and financial situations, and fear that family and friends will become ill. In addition, COVID-19 induced anxiety can cause difficulty sleeping, concentration, memory loss, mood changes, flashbacks, respiratory dysfunction, chest pain, and confusion.

Post-COVID symptoms involve one or more of sleep disturbance, cognitive dysfunction, and anxiety.

Functional magnetic resonance imaging of patients with post-COVID syndrome revealed alterations within and/or between resting-state networks. Most commonly, the default mode network was affected.

Treatment of patients suffering from post-COVID syndrome, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvements in post-COVID syndrome.

Improvement in COVID sequelae (reflected by a decrease in CGI-S scores) is observed at 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; on day 7; on day 14; and/or on day 28.

The improvement of the patient's COVID sequelae (reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement of COVID sequelae (reflected by a decrease in the CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until 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 post-COVID sequelae is reflected at least in an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (reflected in improvement in BIMF total score) in patients with COVID sequelae occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (reflected in improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Idiopathic sleep disorders

Treatment of a patient suffering from idiopathic sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the idiopathic sleep disorder.

Reduction or elimination of idiopathic sleep disturbance 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The reduction or elimination of idiopathic sleep disturbance preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of idiopathic sleep disturbance preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In an embodiment, reduction or elimination of idiopathic sleep disturbance is observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

In the case of idiopathic sleep disorders, the clinical response can be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and/or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and/or to 0 points.

Improvement in idiopathic sleep disturbance (reflected by a decrease in CGI-S score) is observed on day 1, e.g., about 24 hours after; 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.

Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement of idiopathic sleep disturbance (reflected by a decrease in CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In an embodiment, improvement in idiopathic sleep disturbance (reflected by a decrease in CGI-S score) is observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

In the case of idiopathic sleep disorders, improvement in sleep disorders (at least as reflected by a score of "much improved" in 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 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.

Improvement in idiopathic sleep disturbance (at least as reflected by a score of "much improved" on the CGI-I score or the PGI-I score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

The improvement in sleep disturbance (at least as reflected by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In an embodiment, improvement in idiopathic sleep disturbance (at least as reflected by a score of "much improved" in the CGI-I score or the 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 until at least 14 days, more preferably until at least 28 days.

Improvement in idiopathic sleep disturbance may also be assessed by any other scale reflecting changes in sleep quality or quantity as described above, such as the Pittsburgh Sleep Quality Index (PSQI).

If the PSQI is used to assess treatment outcome, treatment success is indicated by (i) a decrease in the total score, preferably (ii) a decrease in the total score to 5 or less. The recall period to be applied begins no earlier than the point in time after the last administration when the acute psychedelic experience has subsided.

Improvement in idiopathic sleep disturbance (as reflected by a decrease in PSQI-S total score, particularly a decrease to 5 or below) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Such improvement in idiopathic sleep disturbance (reflected by a decrease in the PSQI-S total score, in particular a decrease to 5 or below) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in idiopathic sleep disturbance (reflected by a decrease in PSQI-S total score, particularly to 5 or below) 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

In an embodiment, improvement in idiopathic sleep disturbance (reflected by a decrease in the PSQI total score, in particular a decrease to 5 or below) is observed on day 7 and preferably persists until day 14, more preferably until day 28.

Improvement in maternal function in patients suffering from sleep disorders is reflected in at least an improvement in BIMF total score on day 7; day 14; and/or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from sleep disorders occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

Further treatment

Specific aspects of treatment of 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 generally accepted medical practice, wherein the patient is a breastfeeding mother who has been advised to stop breastfeeding until 48 hours, such as 24 hours, preferably 6 hours, more preferably 3 hours, and 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 described 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 described 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 higher, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 17 or higher.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 3, wherein the patient suffers from severe major depressive disorder, as indicated by a MADRS score of 35 or higher, or a HAM-D score of 25 or higher.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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 according to aspects 1 to 5, wherein the patient also suffers from suicidal ideation.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 6, wherein the patient suffers from suicidal ideation and intends to act on it.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 7, wherein the patient is at risk of imminent suicide.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 8, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 9, wherein a dose of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 9, wherein a dose of about 6 mg; or about 12 mg; or about 18 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak psychedelic experience.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg for the first administration, then increased to a dose of about 8 mg to about 14 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 12 to 14, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 2 to 4 hours.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 9 to 15, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, 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 in the Ocean-like Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Psychedelic Experience Questionnaire (PPEQ) total score of at least 75.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 16, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Psychedelic Experience Questionnaire (PPEQ) total score of at least 75.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of the preceding aspects, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 18, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol, the aerosol comprising (a) a pharmaceutically acceptable gas; and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 12.5 mg/l.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 19, wherein the aerosol is generated by: a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to generate aerosol particles.

21. 5-MeO-DMT for use as described in aspects 18 to 20, wherein the 5-MeO-DMT is used in the form of a free base.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 18 to 21, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled via a single breath.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 22, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 23, wherein the clinical response as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score lasts until at least 6 days 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 according to claims 1 to 24, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 14 days 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 according to claims 1 to 25, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 26, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and relief of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 28, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days 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 according to aspects 1 to 29, wherein there is a clinical response at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 30, wherein the patient is in remission of depressive symptoms on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 31, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days 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 described in aspects 1 to 32, wherein there is a clinical response at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 33, wherein the patient is in remission of depressive symptoms on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 34, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days 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 described in aspects 1 to 35, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 36, wherein the patient is in remission of depressive symptoms on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 37, wherein the patient is a lactating woman who is advised to stop breastfeeding until 48 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 according to aspects 1 to 37, wherein the patient is a lactating woman who is advised to stop breastfeeding until 24 hours 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 according to aspects 1 to 37, wherein the patient is a lactating woman who is advised to stop breastfeeding until 6 hours 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 according to any one of claims 1 to 37, wherein the patient is a lactating woman who is advised to stop breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 37, wherein the patient is a lactating woman who is advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 42, wherein said treatment improves maternal function.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 43, wherein the improvement relates to one or more, in particular two or more, functional areas selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 43 or 44, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

Specific aspects of bipolar disorder treatment 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 patient is a breastfeeding mother who is advised to stop breastfeeding until 48 hours, such as 24 hours, preferably 6 hours, more preferably 3 hours, and 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 described in aspect 1, wherein the patient is diagnosed with bipolar disorder type II.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient is diagnosed with bipolar disorder type I.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 3, wherein the patient suffers from a current major depressive episode.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4, wherein the patient has a total score of Montgomery-Asberg Depression Rating Scale (MADRS) equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4 or aspect 5, wherein the patient has a Bipolar Depression Rating Scale (BDRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses of treatment is drug therapy.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of medication.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 8.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 6 mg; or about 12 mg; or about 18 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12, wherein the 5-MeO-DMT or a salt thereof is administered at a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak psychedelic experience.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 14, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg for the first administration, then increased to a dose of about 8 mg to about 14 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 15, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 14 to 16, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 11 to 17, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, 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 in the Ocean-like 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.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 18, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of the preceding aspects, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation, or by nasal, buccal or sublingual administration.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 20, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol, the aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as to about 12.5 mg/l.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 21, wherein the aerosol is generated by: a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to generate aerosol particles.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 20 to 22, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled via a single breath.

24. 5-MeO-DMT for use as described in aspects 20 to 23, wherein the 5-MeO-DMT is used in the form of a free base.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 24, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 25, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 26, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 14 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 described in aspects 1 to 28, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 28 days 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 described in aspects 1 to 29, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 30, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and relief of depressive symptoms is reflected in a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 31, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 32, wherein relief of depressive symptoms is observed on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 33, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days 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 described in aspects 1 to 34, wherein there is a clinical response on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 35, wherein the patient is in remission of depressive symptoms on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 36, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days 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 described in aspects 1 to 37, wherein there is a clinical response on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 38, wherein the patient is in remission of depressive symptoms on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 39, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days 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 described in aspects 1 to 40, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 41, wherein the patient is in remission of depressive symptoms on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 42, wherein the patient does not experience treatment-induced mania or hypomania.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 44, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the first day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

46. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 45, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 46, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 47, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 48, 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 alienation.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 49, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from excessive sleep and the treatment reduces or eliminates the excessive sleep.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 52, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 1st day, e.g., about 24 hours 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 described in aspects 50 to 53, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 7th 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 described in aspects 50 to 54, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 50 to 55, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein said reduction or elimination of sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item sleep disturbance.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 57, wherein said reduction or elimination of sleep disturbances persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score of the MADRS item sleep loss on the first day, e.g., about 24 hours 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 described in aspect 50 or 61, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 7th 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 described in aspect 50, 61 or 62, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 14th day 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 described in aspects 50 or 61 to 63, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 28th day 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 according to aspect 50, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the MADRS item sleep loss.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 65, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours 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 described in aspect 50 or 69, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day 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 described in aspect 50, 69 or 70, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day 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 described in aspects 50 or 69 to 71, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 49, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 73, wherein the improvement in sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point when the acute psychedelic experience resolves after the last dose to the assessment time point.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49 or 77, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point at which the acute psychedelic experience has subsided after the last dose to the assessment time point.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49, 77 or 78, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point at which the acute psychedelic experience has subsided after the last dose to the assessment time point.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 49 or 77 to 79, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point at which the acute psychedelic experience has resolved after the last dose to the assessment time point.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 50, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the total score of the Pittsburgh Sleep Quality Index (PSQI), wherein the recall period is from the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 81, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 84, wherein the patient suffers from psychomotor retardation and the treatment reduces or eliminates the psychomotor retardation.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein the treatment improves or eliminates decreased energy and activity and/or decreased motivation.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 86, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation about 2 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 described in aspects 85 to 87, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 1st day, e.g., about 24 hours 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 described in aspects 85 to 88, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 7th day 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 described in aspects 85 to 89, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 14th day 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 described in aspects 85 to 90, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation on the 28th day 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 described in aspect 85 or 86, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 92, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and/or decreased motivation.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy about 2 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 described in aspect 85 or 96, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness on the first day, e.g., about 24 hours 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 described in aspect 85, 96 or 97, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 7th 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 described in aspects 85 or 96 to 98, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 14th day 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 according to aspects 85 or 96 to 99, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 28th day 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 according to aspect 85, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazy.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 101, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 85, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85 or 105, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 85, 105 or 106, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 85 or 105 to 107, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day 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 described in aspects 85 or 105 to 108, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 84, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 110, wherein the improvement in psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 113, wherein the patient suffers from negative thoughts and the treatment reduces or eliminates the negative thoughts.

115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 114, wherein the treatment reduces or eliminates feelings of worthlessness; helplessness and hopelessness; and/or guilt.

116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt about 2 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 described in aspects 114 to 116, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in scores on the BDRS items worthlessness; helplessness and hopelessness; and/or guilt on day 1, e.g., about 24 hours 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 described in aspects 114 to 117, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt on the 7th day 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 described in aspects 114 to 118, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt on the 14th day 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 described in aspects 114 to 119, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt on the 28th day 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 described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt.

122. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt.

123. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt.

124. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 121, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and/or guilt.

125. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 114 to 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts about 2 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 described in aspects 114, 115 or 125, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 1st day, e.g., about 24 hours 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 described in aspects 114, 115, 125 or 126, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 7th day 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 described in aspects 114, 115 or 125 to 127, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 14th day 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 described in aspects 114, 115 or 125 to 128, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 28th day 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 described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

131. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

132. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

133. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 130, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

134. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt about 2 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 described in aspects 114, 115 or 134, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 1st day, e.g., about 24 hours 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 described in aspects 114, 115, 134 or 135, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt at 7 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 described in aspects 114, 115 or 134 to 136, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 14th day 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 described in aspects 114, 115 or 134 to 137, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 28th day 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 described in aspect 114 or 115, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

140. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

141. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

142. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 139, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

143. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 114 or 115, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 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 described in aspects 114, 115 or 143, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours 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 described in aspects 114, 115, 143 or 144, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day 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 described in aspects 114, 115 or 143 to 145, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day 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 described in aspects 114, 115 or 143 to 146, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 113, wherein the patient suffers from negative thinking and improvement in negative thinking occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

149. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

150. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

151. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 148, wherein said improvement in negative thinking persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

152. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 151, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.

153. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety 2 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 described in aspect 152 or 153, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 1st day, e.g., about 24 hours 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 according to aspects 152 to 154, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 7th day 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 according to aspects 152 to 155, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 14th day 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 according to aspects 152 to 156, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 28th day 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 according to aspect 152, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

159. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

160. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

161. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 158, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

162. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety about 2 hours 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 described in aspect 152 or 162, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 1st day, e.g., about 24 hours 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 described in aspects 152, 162 or 163, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 7th 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 described in aspects 152 or 162 to 164, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 14th day 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 described in aspects 152 or 162 to 165, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 28th day 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 according to aspect 152, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

168. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

169. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

170. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 167, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

171. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 152, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 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 described in aspect 152 or 171, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

173. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 152, 171 or 172, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day 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 described in aspects 152 or 171 to 173, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day 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 described in aspects 152 or 171 to 174, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 151, wherein the patient suffers from anxiety and improvement in anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

177. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

178. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

179. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 176, wherein the improvement in anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

180. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 179, wherein the patient suffers from cognitive dysfunction and the treatment reduces or eliminates the cognitive dysfunction.

181. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment about 2 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 described in aspect 180 or 181, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the first day, e.g., about 24 hours 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 described in aspects 180 to 182, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 7th 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 described in aspects 180 to 183, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 14th day 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 described in aspects 180 to 184, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 28th day 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 according to aspect 180, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items concentration and memory impairment.

187. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items concentration and memory impairment.

188. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

189. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 186, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

190. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating about 2 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 described in aspect 180 or 190, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 1st day, e.g., about 24 hours 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 described in aspects 180, 190 or 191, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 7th day 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 described in aspects 180 or 190 to 192, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 14th day 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 described in aspects 180 or 190 to 193, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 28th day 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 described in aspect 180, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

196. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

197. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

198. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 195, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

199. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 180, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 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 described in aspect 180 or 199, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours 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 described in aspects 180, 199 or 200, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day 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 described in aspects 180 or 199 to 201, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day 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 described in aspects 180 or 199 to 202, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 179, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

205. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

206. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

207. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 204, wherein the improvement in cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

208. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 207, wherein the patient suffers from social/emotional withdrawal or alienation, and the treatment reduces or eliminates the social/emotional withdrawal or alienation.

209. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 208, wherein the treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

210. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy about 2 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 described in aspects 208 to 210, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or apathy on the 1st day, e.g., about 24 hours 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 described in aspects 208 to 211, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 7th day 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 described in aspects 208 to 212, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 14th day 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 described in aspects 208 to 213, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy on the 28th day 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 described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

216. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 215, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy.

217. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 215, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or emotional apathy.

218. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 215, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and/or affective apathy.

219. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss about 2 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 described in aspects 208, 209 or 219, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 1st day, e.g., about 24 hours 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 described in aspects 208, 209, 219 or 220, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 7th day 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 described in aspects 208, 209 or 219 to 221, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 14th day 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 described in aspects 208, 209 or 219 to 222, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 28th day 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 described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item sensory loss.

225. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

226. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

227. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 224, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

228. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal about 2 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 described in aspects 208, 209 or 228, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 1st day, e.g., about 24 hours 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 described in aspects 208, 209, 228 or 229, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 7th day 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 described in aspects 208, 209 or 228 to 230, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 14th day 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 described in aspects 208, 209 or 228 to 231, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 28th day 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 described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item emotional withdrawal.

234. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

235. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

236. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 233, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

237. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness about 2 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 described in aspects 208, 209 or 237, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunted affect at day 1, e.g., about 24 hours 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 described in aspects 208, 209, 237 or 238, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunting on the 7th day 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 described in aspects 208, 209 or 237 to 239, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 14th day 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 described in aspects 208, 209 or 237 to 240, wherein said reduction or elimination of social/emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 28th day 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 described in aspect 208 or 209, wherein said reduction or elimination of social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item blunted affect.

243. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

244. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

245. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 242, wherein said reduction or elimination of social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

246. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 208 or 209, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

247. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

248. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209, 246 or 247, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

249. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246 to 248, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

250. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 208, 209 or 246 to 249, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

251. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 207, wherein the patient suffers from social/emotional withdrawal or alienation and improvement in social/emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

252. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

253. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

254. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social/emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

255. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 254, wherein the treatment reduces or eliminates suicidal ideation.

256. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation about 2 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 described in aspect 255 or 256, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 1st day, e.g., about 24 hours 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 described in aspects 255 to 257, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 7th day 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 described in aspects 255 to 258, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 14th day 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 described in aspects 255 to 259, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 28th day 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 according to aspect 255, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item suicidal ideation.

262. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

263. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

264. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 261, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

265. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item Suicidal Thoughts about 2 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 described in aspect 255 or 265, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the first day, e.g., about 24 hours 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 described in aspects 255, 265 or 266, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 7th day 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 described in aspects 255 or 265 to 267, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 14th day 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 described in aspects 255 or 265 to 268, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 28th day 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 according to aspect 255, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item Suicidal Thoughts.

271. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

272. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

273. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 270, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

274. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 255, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

275. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255 or 274, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

276. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 255, 274 or 275, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

277. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 274 to 276, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

278. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 255 or 274 to 277, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day 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 described in aspects 1 to 254, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

280. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

281. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

282. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 279, wherein the improvement in suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

283. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 282, wherein the treatment reduces or eliminates at least one of psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

284. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 283, wherein the patient is a lactating woman who is advised to stop breastfeeding until 48 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 described in aspects 1 to 283, wherein the patient is a lactating woman who is advised to stop breastfeeding until 24 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 described in aspects 1 to 283, wherein the patient is a lactating woman who is advised to stop breastfeeding until 6 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 described in any one of claims 1 to 283, wherein the patient is a lactating woman who is advised to stop breastfeeding until 3 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 described in aspects 1 to 283, wherein the patient is a lactating woman who is advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

289. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 288, wherein the treatment improves maternal function.

290. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 289, wherein the improvement relates to one or more, in particular two or more, functional areas selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

291. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 289 or 290, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

Example

The following examples are set forth to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit the invention described in the claims that follow in any manner.

Example 1-5 - MeO-DMT Aerosol Generation and Administration

Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask so that a 200 μl solution volume contains the target dose of 5-MeO-DMT free base to be administered to the volunteer or patient via inhalation. A typical target dose is 1 mg to 25 mg 5-MeO-DMT. For example, for a target dose of 18 mg 5-MeO-DMT, dissolve 90 mg of 5-MeO-DMT in 100% ethanol in a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

Step 2: 200 μl of the solution was transferred into a dosing capsule (Storz & Bickel, Germany) containing a drip pad and then the lid of the dosing capsule was closed.

Step 3: The dosing capsules filled with the 5-MeO-DMT ethanol solution were transferred to the filling chamber of the first Volcano Medic vaporizer, which was preheated and set to 55°C. The gas flow of the vaporizer was then turned on for 60 seconds at a preset rate of approximately 12 l/min. The heated air would flow through the dosing capsules, allowing the ethanol to evaporate, while the target dose of 5-MeO-DMT remained in the capsules as a thin layer covering the stainless steel mesh. The accurate preparation of the dosing capsules was confirmed by demonstrating that the final weight gain of the capsules was approximately equal to the target dose of 5-MeO-DMT compared to the empty capsule weight.

Step 4: Remove the prepared dosing capsule from the filling chamber. It is then transferred to the filling chamber of a second VolcanoMedic vaporizer, which has been preheated, set to 210°C, and the airflow is turned on for at least 5 minutes, then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is installed on the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately turned on at a preset flow rate of approximately 12 1/min for 15 seconds and then turned off. This will allow the entire dose of 5-MeO-DMT to be aerosolized and distributed in the approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to approximately its initial weight.

Step 5: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After the mouthpiece is connected to the balloon, the aerosol is ready to be immediately administered to the volunteer or patient.

Step 6: To prepare for administration, ask the patient to first take 1-2 deep breaths, exhale completely, and end the process with a deep exhalation. Then, hold the mouthpiece firmly against the lips, inhale the entire volume of the balloon in one breath, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020/169850A1, 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 volumes) at 35 to 40 ° C and then cooled to room temperature within 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed, so the batch temperature was reduced to 7 to 12 ° C within 30 minutes. Crystallization occurred after stirring at 7 to 12 ° C for 10 minutes. It was then stirred at 7 to 12 ° C for 1 hour, and the batch was subsequently filtered. After washing with MTBE (1 mL, 0.5 volumes) at 7 to 12 ° C, the batch was dried under vacuum for 3.5 hours to obtain 1.02 g of light orange solid (50% recovery). As described in WO 2020/169850 A1, the purity of the separated solid was analyzed by HPLC. The purity is 99.74% area.

The analytical results further indicated that the level of individual impurities was less than 0.10% area. Solvent analysis of the sample indicated MTBE level was 17 ppm.

Example 3-5-Preparation of MeO-DMT Hydrobromide

5-MeO-DMT HBr was prepared on 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 charged in a single aliquot. The mixture was maintained at this temperature and equilibrated for 3 hours.

After 1 hour, a suspension was formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuo at 40°C for 18 hours.

An off-white crystalline material was obtained.

The salt has a melting point of 174°C and is characterized in that it has an X-ray diffraction pattern comprising peaks at 14.5°2·±0.2°2·; 16.7°2·±0.2°2·; 17.0°2·±0.2°2·; 20.6°2·±0.2°2·; 20.7°2·±0.2°2·; 21.4°2·±0.2°2·; 24.2°2·±0.2°2·; 24.8°2·±0.2°2·; 25.3°2·±0.2°2·; 27.4°2·±0.2°2·; which is measured using Cu K· radiation.

Example 4 - Determination of Inhibition Constants of Central 5-HT1A and 5-HT2A Receptors in Postmortem Human Brain Membranes Preparations

In the present study, the affinity of three psychedelic test compounds (psilocybin dephosphate, DMT, and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue (from the hippocampus and frontal cortex, respectively) was determined using radioligand binding techniques.

Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors died suddenly, had no history of coma, psychiatric or neurological disease, were under 65 years old, and had a postmortem interval of less than or equal to 72 hours.

Binding to 5-HT1A receptors in postmortem human hippocampus

The hippocampus was homogenized in ice-cold 0.25M sucrose (1:30 weight/volume) using an electric Teflon pestle (grinded 12 times at 120rpm). Myelin and cell debris were removed by centrifugation at 1,000g for 10 minutes. The supernatant was stored on ice, and the precipitate was homogenized again in 0.25M sucrose (1:15 weight/volume) and centrifuged at 750g for 10 minutes. The supernatant was merged and diluted with ice-cold membrane preparation buffer (1:100 weight/volume), using a tightly fitting glass/Teflon homogenizer (12 times, 800rpm), and centrifuged at 20,500g for 10 minutes. The precipitate was resuspended in ice-cold membrane preparation buffer, and incubated at 37°C for 10 minutes, then centrifuged at 20,500g for 10 minutes. The precipitate was resuspended and centrifuged for the last time to wash the tissue (20,500xg, 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equal to 3.125 mg tissue wet weight/ml. All centrifugations were performed at 4°C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl ₂ , and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl ₂ , 0.1% ascorbic acid, and 10 μM Pargyline.

For saturation binding analysis, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue/tube) were incubated with 50 μl 0.075–9.6 nM [ ³ H]8-OH-DPAT and either 50 μl assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

In the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue/tube) were incubated with 50 μl 0.6 nM [ ³ H]8-OH-DPAT and either 50 μl assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 30 min at 25°C.

Membrane-bound radioactivity was recovered by vacuum filtration through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. The filters were quickly washed with ice-cold wash buffer (wash settings 0,9,9) and radioactivity was determined by liquid scintillation counting (1 ml Packard MV Gold scintillation counter).

Nonlinear regression was used to calculate the compound concentration required to inhibit 50% of specific binding ( _IC50 ) and the Hill slope.K1 was calculated using a one-site binding _model allowing for ligand depletion.

Binding to 5-HT2A receptors in postmortem human frontal cortex

The frontal cortex was homogenized in ice-cold 0.25M sucrose (1:30 weight/volume) using an electric Teflon pestle (grinding 12 times at 120rpm). Myelin and cell debris were removed by centrifugation at 1,000g for 10 minutes. The supernatant was stored on ice, and the precipitate was homogenized again in 0.25M sucrose (1:15 weight/volume) and centrifuged at 750g for 10 minutes. The supernatant was merged and diluted with ice-cold 50mM Tris-HCl assay buffer, pH 7.4 (1:100 weight/volume), homogenized using a tightly fitting glass/Teflon homogenizer (12 times, 800rpm), and centrifuged at 20,500g for 10 minutes. The precipitate was further centrifuged twice to wash the tissue (20,500x g, 10 minutes). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, with a tissue concentration equal to 10 mg tissue wet weight/ml. All centrifugations were performed at 4°C.

For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight/tube) were incubated with 50 μl 0.00625–0.8 nM [ ³ H]MDL-100,907 and either 50 μl assay buffer or 50 μl 10 μM ketanserin (nonspecific binding) for 60 min at 25° C. Assay and wash buffers consisted of 50 mM Tris-HCl buffer, pH 7.4.

In the displacement assay, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight tissue/tube) were incubated with 50 μl of 0.1 nM [3H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 60 min at 25°C.

Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

result

The dissociation constants (K _d values) of [ ³ H]8-OH-DPAT and 5-HT1A receptors in the hippocampal membrane of postmortem human brain tissue from three donors were determined. The dissociation constants (K _d values) obtained were 0.51, 0.28, and 0.52 nM, respectively.

The average inhibition constants ( _Ki values) for dephosphopsilocybin, DMT, and 5-MeO-DMT were 48, 38, and 1.80 nM, respectively (average n=3). The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

The dissociation constants (K _d values) of [ ³ H]MDL-100,907 and 5-HT2A receptors in the frontal cortex membranes of postmortem human brain tissue from three donors were determined. The dissociation constants (K _d values) obtained were 0.11, 0.08, and 0.08 nM, respectively.

The average inhibition constants ( _Ki values) for dephosphopsilocybin, DMT, and 5-MeO-DMT were 37, 117, and 122 nM, respectively (average n=3). The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

The selectivity ratios of dephosphorylated psilocybin, DMT, and 5-MeO-DMT for 5-HT2A receptors over 5-HT1A receptors are 0.78, 3.1, and 68, respectively.

Example 5 - Clinical Trial in Patients Suffering from TRD

A Phase 1/2 clinical trial of 5-MeO-DMT administered via inhalation as described herein has been completed in patients with treatment-resistant major depressive disorder (TRD). This trial is designed in two parts. Part A is an open-label, single-arm, single-dose Phase 1 trial with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B is an open-label, single-arm Phase 2 trial with an individualized dosing regimen and a step-wise increase in the 5-MeO-DMT dose within the patient. Patients (n=8) receive at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) per day, with higher doses only being administered when the previously administered dose does not achieve a peak experience. The primary endpoint of Part A is to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in TRD patients. The primary endpoint of Part B is to evaluate the effect on depression severity, as assessed by the proportion of patients who are relieved on the seventh day after administration, with relief defined as a total MADRS score of less than or equal to 10.

In Part A, 3 of 4 patients in both groups (12 mg and 18 mg) experienced at least one 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 after dosing, and another patient (25%) in the 18 mg group had MADRS clinical response on day 7 after dosing. 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 ADR. All ADRs resolved spontaneously. No SAEs were reported.

At day 7, seven of eight patients (87.5%) achieved MADRS remission, achieving the primary endpoint (p<0.0001). The mean MADRS change from baseline at day 7 was 24.4 (76%).

No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or measures of cognitive function in Part A or Part B.

The results are summarized in the table below.

Table 2-A Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment 2 hours (MADRS) or 3 hours (BPRS) after administration of the last dose.

Table 2-B Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 1.

Table 2-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 7.

Table 3-A Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment 2 hours (MADRS) or 3 hours (BPRS) after dose administration.

Table 3-B Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 1.

Table 3-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 7.

Example 6-5-Pharmacokinetic Evaluation of MeO-DMT and Toxoplasmamine

To study the pharmacokinetic properties of 5-MeO-DMT, three groups of 8 subjects were divided. Subjects were administered a single dose of 6 mg, 12 mg, or 18 mg 5-MeO-DMT via inhalation. Blood samples were obtained at 1, 2, 4, 7, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, and 4 hours after administration, respectively.

5-MeO-DMT concentrations were determined using LC-MS/MS. PK parameters were generated by algebraic analysis of concentration versus time plots for each individual. Analysis was 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), respectively.

Table 4 below shows the median percentage of plasma concentration relative to Cmax determined at the indicated time points.

Pharmacokinetic measurements were also performed for a dosing regimen that relied on up-titration, and substantially similar results were obtained.

The blood concentration of the 5-MeO-DMT metabolite bufotoxin was also determined. Only in a few samples were the concentrations above the lower limit of quantification (LLOQ) (25 pg/ml). From 15 minutes onwards, the bufotoxin concentrations were always below the LLOQ.

Essentially similar observations were made when subjects who received an up-titration regimen were included.

Example 7-5-Toxicology Testing of MeO-DMT

5-MeO-DMT did not induce mutations in four histidine-requiring 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 concentrations up to 5000 μg/plate (the maximum concentration recommended according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

Example 8-5-Binding of MeO-DMT to human plasma proteins

In vitro binding of 5-MeO-DMT to plasma proteins was determined using high throughput dialysis. Equilibrium times and nonspecific binding were determined using human plasma at a nominal 5-MeO-DMT concentration of 1 μM. After evaluation of the equilibrium data, plasma protein binding was studied at nominal concentrations of 0.1, 1, and 10 μM using a 4 hour dialysis time. The concentration of 5-MeO-DMT in samples from the plasma and buffer compartments was determined by LC-MS/MS. The protein binding results are shown below:

Table 5 Percentage of 5-MeO-DMT free fraction in human plasma

5-MeO-DMT(μM) Free fraction, % 0.1 78.7 1 77.3 10 87.0

Example 9-5-Human Metabolism of MeO-DMT

Nominal concentrations of 1 μM and 10 μM of 5-MeO-DMT were incubated with human hepatocytes (1×10 6 cells/mL) suspended in Leibovitz L-15 medium.

A 20 mM 5-MeO-DMT standard stock solution was prepared in ethanol and further diluted to a concentration of 2 mM with 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 with Leibovitz L-15 medium. Aliquots (250 μL) of the 20 μM and 2 μM test substance preparations were appropriately added to each hepatocyte incubation sample (250 μL) so that the final test substance concentration in the incubation solution was 10 μM or 1 μM, respectively, and the incubation solution contained less than 1% (volume/volume) of solvent.

Incubations were performed in a shaking water bath at approximately 37°C (total incubation volume was 0.5 mL). For 1 μM, incubations were terminated after 0, 5, 10, 20, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile (0.5 mL). For 10 μM, incubations were terminated after 0, 10, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile containing an internal standard (1 μg/mL dephosphopsilocybin-d10).

The samples were vortexed 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 incubations were performed using Leibovitz L-15 medium instead of the test substance. For the cell-free control samples, Leibovitz L-15 medium was used instead of the hepatocytes. Aliquots of the blank control samples were taken at 120 minutes, while for the 1 μM incubations, cell-free control samples were taken at 0, 30 and 120 minutes, and for the 10 μM incubations, cell-free control samples were taken at 0 and 120 minutes.

All 1 μM incubations were performed in duplicate, while all 10 μM incubations were performed in single runs. All samples were stored at -80°C (nominal) prior to analysis.

Developed suitable chromatographic conditions to retain the parent compound and give suitable chromatographic response. 0, 30 and 120 minutes of incubation samples produced after 10 μM 5-MeO-DMT incubation were analyzed using reversed phase LC-MS analysis to generate high energy and low energy mass spectra (MSE). Before sample analysis, 100 μL aliquots of each sample were evaporated to near dryness at room temperature under a stable nitrogen stream, and then redissolved in 50 μL 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 level of the parent compound at each time point, and to determine the profile of the metabolites formed. Appropriate blank samples and control samples were also analyzed. 10 μM incubation samples at 10 minutes and 60 minutes were not analyzed and stored at -80°C (nominal).

The presence of metabolites in the data was queried using screening software (UNIFI version 1.9.4) and user-defined search parameters by comparing retention times to test substance reference standards and based on the accurate masses of potential metabolites. To confirm suspected metabolites, the measured accurate mass of peaks detected in samples for structural elucidation had to be within 5 ppm of the theoretical mass to confirm the molecular formula.

Table 1 above summarizes the results obtained.

Example 10- Metabolic stability of 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptol in a human hepatocyte co-culture model

The metabolic stability of 5-MIAA and 5-methoxytryptol was investigated in a Hμrel co-culture assay with human hepatocytes (Hμrel HumanPool ^™ , a primary liver co-culture model from Visikol Inc.).

Incubations were performed using 1 and 10 μM initial concentrations and samples were taken at 0, 1, 2, 4, 8, 24, 48 and 72 hours (h) time points. The samples were analyzed using UPLC/QE-orbitrap-MS.

The table below shows the remaining LC/MS peak area of the test compounds detected using the Hμrel co-incubation assay after each incubation time point relative to the corresponding 0 min incubation sample. The results of the control diazepam assay (disappearance half-life) indicated that the enzyme activity was within normal levels.

Table 6 - Relative LC/MS peak areas of 5-MIAA after 0-72h incubation. Initial substrate concentrations were 1 and 10 μM (n=2 at 1 μM, n=1 at 10 μM).

Table 7 - Relative LC/MS peak areas of 5-methoxytryptol after 0-72 h incubation. Initial substrate concentrations were 1 and 10 μM (n=2 at 1 μM, n=1 at 10 μM).

A low metabolic turnover of 5-MIAA was observed, with a residual abundance of 75-82% after 72 h in the presence of hepatocytes, whereas no disappearance was observed in stromal cell controls.

For 5-methoxytryptol, a high metabolic turnover was observed, with complete disappearance within 24 h in the presence of hepatocytes but not in stromal cell controls.

Using human hepatocytes and a 1 μM test concentration, the in vitro intrinsic clearance of 5-MIAA was 0.15 μl/min/million cells (half-life 15 400 min), while the corresponding value for 5-methoxytryptol was 16.2 μl/min/million cells (half-life 142 min).

The predicted hepatic extractability of 5-MIAA is 2% and that of 5-methoxytryptol is 67%.

Example 11-5-Plasma Binding of MIAA

Binding to human plasma proteins was determined. Unbound scores (fu) from triplicate experiments are reported as well as the mean unbound score, standard deviation and mean % recovery (Table 8).

Example 12 - Clinical Trial of Administering 5-MeO-DMT to Patients with Postpartum Depression via Inhalation

This single-arm, open-label clinical trial will involve 15 adult female patients clinically diagnosed with postpartum depression (PPD).

Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

2. The second dose (12 mg) will be administered only in the following cases:

a. Peak experience (total score ≥ 75) not achieved after 6 mg dose, and

b. According to the researchers, the 6 mg dose was safe and well tolerated.

c. Any psychoactive effects (PsE) from the previous dose have resolved, and

d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

3. Similarly, the third dose (18 mg) will only be administered if:

a. Peak experience not achieved after 12 mg dose (total score ≥ 75), and

b. According to the researchers, the 12 mg dose was safe and well tolerated, and

c. Any PsE from the previous dose has resolved, and

d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

All patients considered for participation in a clinical trial must meet the following criteria:

1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

2. Body mass index (BMI) at screening is within the range of 18.5 to 35 kg/ ^m2 (inclusive).

3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express/discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

4. Must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods for 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day -1).

5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic 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 unsuitable for the trial.

2. One or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

11. Patient has a positive pregnancy test at Screening or the day before testing (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

The primary objective of the trial was to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 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, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening could be performed as needed) following single-day administration of a single individualized IDR (6 mg, 12 mg, and 18 mg 5-MeO-DMT) to adult female PPD patients as measured by LC/MS/MS.

The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

Secondary endpoints included evaluation of the antidepressant effects of 5-MeO-DMT by:

The antidepressant effects of 5-MeO-DMT were evaluated by:

○ Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

○ Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

○ Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

○ Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

To evaluate the safety and tolerability of 5-MeO-DMT by:

○ Report treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak flow spirometry;

○ Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA/S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

○ Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

○ Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

○ Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

○ Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

○ PsE assessment using the Peak Experience (PE) scale to assess the achievement of PE (PE scale total score ≥ 75);

○ Challenging Experience Questionnaire (CEQ);

○Mystical Experience Questionnaire (MEQ-30);

Duration of PsE was defined as the time from the time of study drug administration to the time when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose;

Currently, one patient diagnosed with postpartum depression by a psychiatrist has been recruited to participate in the clinical trial. The diagnosis of major depressive disorder without psychotic features was confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2) with perinatal onset no earlier than during pregnancy and no later than the first 4 weeks postpartum. The patient was diagnosed with postpartum depression after the birth of her third child. The patient completed all scheduled clinic days. The inhalation procedure was adequately performed by the patient and well tolerated, with no adverse events related to the inhalation.

result

No other noteworthy changes in vital parameters occurred, except for a transient, clinically insignificant increase in heart rate and blood pressure shortly after 5-MeO-DMT administration. ECG (3 hours after administration) and safety laboratory analysis (7 days), CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (left abdominal cramping pain and headache, both on day 0) were mild, transient, and resolved spontaneously by the end of the study.

Regarding the intensity of the psychedelic experience, the PES score achieved upon exposure to the nominal dose of 6 mg was recorded to be 17.3. This score indicates that a subsequent higher dose of 12 mg is required as per the design of the individualized dosing regimen. The PES score achieved at this dose was 85.7 and ≥75, indicating that this patient experienced a peak psychedelic experience and completed the IDR.

Importantly, patients reported significant improvements in their depressive symptoms, as assessed by MADRS at the earliest assessment time point (2 hours) after drug administration, and the effect was maintained over time (Table 9). Patients also met the criteria for MADRS response (at least 50% improvement relative to baseline) and MADRS remission (MADRS total score equal to or less than 10).

Table 9-MADRS/BPRS scoring table

Significant improvements were noted in particular for several MADRS items. The individual items are summarized in Table 9. Patients had baseline scores for several items that reflected the absence of symptoms (decreased appetite, difficulty concentrating, suicidal thoughts), while scores for items that reflected severe symptoms (e.g., decreased sleep, inner tension) improved significantly.

Likewise, several BPRS items improved, including somatic problems, anxiety, emotional withdrawal, guilt, and tension.

Additionally, as summarized in Table 10, improvements in maternal function were demonstrated by the improvement in BIMF scores recorded on Day 7, with the total score increasing from 92 to 105, an improvement of 14% (total score can be 120).

Several domains of maternal functioning as defined by Barkin et al were also assessed. Table 11 summarizes the improvements in each domain of functioning in more detail.

Here, significant improvements in self-care, mental health and management were achieved, with % improvements ranging from 18% (management) to (44%) % (self-care). These improvements reinforced the relationship between improvements in depression items, as assessed by MADRS and improvements in maternal functioning.

It is noteworthy that the patient's scores were relatively high before treatment. In some functional areas, the scores were at or near the maximum (see Table 11), making the scope for improvement through treatment limited.

Table 10-BIMF score table

Table 11-BIMF functional area scoring table

Summary and Conclusion

A. An individualized dosing regimen of 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT via inhalation was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

B. Rapid clinical response within 2 hours after 5-MeO-DMT administration. This rapid onset of action is not common and has not been seen in traditional antidepressant classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSR1), serotonin-norepinephrine reuptake inhibitors (SNR1), etc., which usually require 4 to 6 weeks to show effects.

C. According to the IDR, the patient experienced clinical remission within 2 hours of 5-MeO-DMT administration. This is superior to any approved treatment for postpartum depression as well as all previously tested psychedelics.

D. Although 5-MeO-DMT was only administered once and is no longer effectively present in the body within this time frame (see pharmacokinetic data in Example 6 above), a significant clinical response persisted over the 7-day follow-up period. This observation supports the superior clinical profile of 5-MeO-DMT and allows for convenient dosing intervals.

E. In addition to the antidepressant effects, endpoints assessing other symptoms (such as somatic problems, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

F. In addition to the antidepressant effects, endpoints assessing maternal functioning such as self-care, psychological well-being, and management assessed using the BIMF were also positively affected, supporting the idea that 5-MeO-DMT has additional benefits beyond improving core depressive symptoms in patients with PPD.

The salient aspects demonstrate that, when used in accordance with the present invention, 5-MeO-DMT has significantly improved efficacy compared to approved pharmacotherapy for postpartum depression and all previously tested psychedelics.

Combined with the short duration of the acute psychedelic effect and the favorable safety profile, these data suggest that the present invention solves the technical problem of providing improved psychoactive therapies for patients with postpartum depression.

Example 13 - Clinical Trial of Administering 5-MeO-DMT to Bipolar II Patients via Inhalation

This single-arm, open-label clinical trial will involve 15 adult patients with bipolar II disorder and a current major depressive episode.

Patients currently taking antidepressant medications need to stop taking them or taper off the medication over time.

Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

More specifically, patients will receive up to three doses of 5-MeO-DMT on the administration day (Day 0): 6 mg, 12 mg, and 18 mg.

1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

2. The second dose (12 mg) will be administered only in the following cases:

a. Peak experience not achieved after 6 mg dose (PES total score ≥ 75), and

b. The 6 mg dose was safe and well tolerated.

3. Similarly, the third dose (18 mg) will only be administered if:

a. Peak experience not achieved after 12 mg dose (PES total score ≥ 75), and

b. The 12 mg dose was safe and well tolerated.

The patients’ peak psychedelic experience will be assessed based on the patient-rated PES described above, sedation after dosing, and other endpoints. Follow-up visits are planned on days 1 and 7 after dosing.

Patient selection was based on the following key inclusion criteria:

1. Understand the nature of the clinical trial and provide signed and dated written informed consent in accordance with local regulations before any trial-related procedures are carried out.

2. Male or female, aged between 18 and 64 years old (inclusive) at the time of screening.

3. Meets trial criteria for bipolar disorder type II and is experiencing a major depressive episode as assessed by the trial psychiatrist or registered clinical psychologist:

a. Meet the diagnostic criteria for bipolar II disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and be confirmed to have a current episode of major depressive disorder by the Mini-International Neuropsychiatric Interview (MINI);

b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 24 at screening and before the first dose on Day 0;

4. The total score of the Young's Mania Rating Scale (YMRS) is less than or equal to 8 at screening and before the first dose on day 0;

5. Agree to keep any psychotherapy unchanged and not start any new psychoactive medications during the trial.

6. Female patients must be surgically sterilized (hysterectomy, tubal ligation, or bilateral oophorectomy (6 months before screening)), or be postmenopausal and have achieved amenorrhea or complete abstinence (complete avoidance of heterosexual intercourse) in the past 2 years, or use a medically approved highly effective (failure rate <1%) contraceptive method 30 days before and 90 days after 5-MeO-DMT administration, including but not limited to bilateral tubal ligation/blockage, hormonal contraceptives that suppress ovulation, intrauterine devices (including hormone-releasing intrauterine devices/systems), and must have a negative serum pregnancy test at screening and a negative urine pregnancy test on the day before the test (day -1).

7. Male patients must use preventive contraception (i.e., use of condoms containing spermicide or abstinence) and must not donate sperm within 30 days of 5-MeO-DMT administration.

Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder type I, manic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic 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 unsuitable for the trial.

2. One or more first- or second-degree relatives currently or previously diagnosed with a psychotic disorder, bipolar disorder type I, or MDD with psychotic features.

3. Significant suicide risk, defined as: (a) suicidal ideation as described in C-SSRS Item 4 or 5 within the past year, during the screening period, or at baseline; or (b) suicidal behavior within the past year; or (c) clinical assessment of significant suicide risk during the clinical interview; or (d) non-suicidal self-injurious behavior within the past year.

4. Taking antidepressants within 7 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

5. Taking drugs with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) before administration.

6. Received mood stabilizer therapy (e.g., lamotrigine, valproate, atypical antipsychotics) within 14 days (28 days for lithium) or 5 half-lives (whichever is longer) prior to dosing, or received mood stabilizer therapy at screening, or is expected to require mood stabilizer therapy during the study (based on the investigator's judgment).

7. Previous serious adverse reactions to hallucinogens or psychedelic drugs, as determined by the investigator.

8. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

9. Suffering from any current or past clinically significant illness (e.g., severe infection, severe lung disease, uncontrolled hypertension, uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness) that may interfere with the interpretation of the trial results, pose a risk to the patient's health, or make the patient unsuitable for participation in the trial according to the investigator's judgment.

10. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

11. Clinically significant abnormalities in physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

12. Female patients with a positive pregnancy test at screening or the day before testing (Day -1), are pregnant or breastfeeding, or plan to become pregnant during the course of the trial and up to 30 days after 5-MeO-DMT administration.

13. Patients with DSM-5, alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

The primary objective of the trial was to determine the onset and duration of antidepressant effects of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in patients with bipolar II disorder and a current major depressive episode. Secondary objectives were to determine the effects of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) on depressive symptoms and global clinical status in patients with bipolar II disorder and a current major depressive episode; safety and tolerability; the effects on the intensity and duration of psychoactive effects (PsE); the effects on sleep quality; and the effects on cognitive outcomes.

The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

Secondary endpoints include:

The antidepressant effects of 5-MeO-DMT administered via inhalation were evaluated by:

○ Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

○ Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

○ Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

○ Change from baseline in CGI-S assessed 2 hours after the final study drug dose on Day 0 and on Days 1 and 7;

○ Change from baseline in BDRS at Day 1 and Day 7

To evaluate the safety and tolerability of 5-MeO-DMT administered by inhalation by:

○ Report treatment-emergent adverse events (TEAEs);

○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and spirometry assessments;

○ Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA/S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

○ The incidence of adverse events (AEs) of mania or hypomania (assessed using DSM-5 criteria for mania/hypomania);

○ Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

○ Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

○ Assess patient readiness for discharge on discharge day 0 using the Clinical Assessment of Discharge Readiness (CADR);

○ Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

○ C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA).

Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

○ PsE assessment using the Peak Experience (PE) Scale (PES) to assess the achievement of PE (PES total score ≥ 75);

○ Challenging Experience Questionnaire (CEQ);

○Mystical Experience Questionnaire (MEQ-30).

Duration of PsE was defined as the time from study drug administration to when PsE had resolved, which was completed within 30 to 60 minutes after each dose;

Effect on sleep quality, as assessed by the change in the Pittsburgh Sleep Quality Index (PSQI) from the day before testing (Day -1) to Day 1 and to Day 7.

Effects on cognitive outcomes, as assessed by change from the day before testing (Day -1) to discharge 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).

Claims (32)

1. 5-Methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a mental or neurological disorder in a mother who has a child of 18 months or less.
2. 2. The 5-MeO-DMT for use according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the mental or neurological disorder involves one or more symptoms selected from sleep disorders, cognitive dysfunction, anxiety, bradykinesia, social/emotional withdrawal and negative thinking.
3. 3. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 1 or 2, wherein the patient is suffering from a therapeutically resistant form of the disorder.
4. 4. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 3, wherein about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, for example after about 24 hours; day 7; day 14; and/or an improvement in the disorder is observed on day 28, the improvement being reflected in a decrease in CGI-S score.
5. 5. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 3, wherein the improvement in the disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected in a decrease in CGI-S score.
6. 6. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 3 or 5, wherein the improvement of the disorder continues until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular at least 14 days until the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably at least 28 days until after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement is reflected in a decrease in CGI-S score.
7. 7. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1to 6, wherein the patient also suffers from mildly impaired, impaired or severely impaired maternal function.
8. 8. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claim 7, wherein the patient has a Barkin maternal functional index (BIMF) score of 95 or less, such as 80 or less, particularly 65 or less.
9. 9. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 8, wherein the treatment improves maternal function.
10. 10. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 9, wherein the improvement relates to one or more, in particular two or more, functional areas selected from self care, baby care, mother-child interaction, mental health, social support, management and regulation of the mother according to Barkin mother's functional index (BIMF).
11. 11. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 8 to 10, wherein the BIMF score is improved by 10% or more, preferably 20% or more.
12. 12. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 11, wherein the 5-MeO-DMT or salt thereof is administered at a dose or dose regimen that causes the patient to experience a peak fantasy experience.
13. 13. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 12, wherein a dose of about 4mg to about 20mg of 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.
14. 14. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 1 to 12, wherein about 6mg is administered; or about 12mg; or a dose of about 18mg, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.
15. 15. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1 to 13, wherein the 5-MeO-DMT or salt thereof is administered at a first dose upon first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak illusive experience.
16. 16. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use of claims 1-15, wherein the 5-MeO-DMT is administered at a dose of about 2mg to about 8mg at a first administration, then increases to a dose of about 8mg to about 14mg at a second administration unless the patient has experienced a peak vague experience, then increases to a dose of about 14mg to about 20mg at a third administration unless the patient has experienced a peak vague experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.
17. 17. The 5-MeO-DMT for use of claim 16, or a pharmaceutically acceptable salt thereof, wherein the first dose of 5-MeO-DMT is about 6mg, the second dose of 5-MeO-DMT is about 12mg, and the third dose of 5-MeO-DMT is about 18mg; or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.
18. 18. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claims 15 to 17, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.
19. 19. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 12 to 18, wherein the occurrence of the peak fantasy experience is identified by reaching at least 60% of the highest possible score in each of the four sub-scales (mystery, active emotion, override time and space and self-evident) of the 30 project revised mystery experience questionnaire (MEQ 30), or by reaching at least 60% of the highest possible score of the marine-like borderless (OBN) dimension in the state of consciousness change (ASC) questionnaire, or by reaching at least 75 Peak Experience Scale (PES) total score.
20. 20. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to claim 19, wherein the occurrence of peak illusion experience is identified by reaching a Peak Experience Scale (PES) score of at least 75.
21. 21. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 20, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation, or by nasal, buccal or sublingual administration.
22. 22. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 21, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas; (b) Aerosol particles of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of from about 0.5mg/l to about 18mg/l, such as to about 12.5 mg/l.
23. 23. The 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use of claim 22, wherein the aerosol is generated by: a) Exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to produce aerosol particles.
24. 24. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 21 to 23, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled by a single breath.
25. 25. The 5-MeO-DMT for use according to claims 21 to 24, wherein the 5-MeO-DMT is used in the form of a free base.
26. 26. The 5-MeO-DMT for use according to claims 1 to 25, wherein the disorder is a disorder characterized by depressive episodes, such as Major Depressive Disorder (MDD), persistent depressive disorder, seasonal affective disorder, and bipolar affective disorder (BD), such as bipolar affective disorder type I and bipolar affective disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized Anxiety Disorder (GAD), social Anxiety Disorder (SAD), panic disorder, phobia, and substance/drug induced anxiety disorder; somatic symptom disorder; obsessive compulsive disorder and related disorders such as Obsessive Compulsive Disorder (OCD) and physical deformity disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders such as chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from the use of psychoactive substances, such as Substance Use Disorder (SUD); psychotic disorders, such as schizophrenia; eating disorders; attention Deficit Hyperactivity Disorder (ADHD); personality disorders, such as split personality disorders and borderline personality disorders; autism spectrum disorder; chronic fatigue syndrome; mental or neurological disorders associated with HIV, covd sequelae, or traumatic brain injury.
27. 27. The 5-MeO-DMT for use of claims 1 to 26, wherein the patient suffers from sleep disorders.
28. 28. The 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the patient is a breast-feeding mother who is advised to stop breast-feeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
29. 29. The 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the patient is a breast-feeding mother who is advised to stop breast-feeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
30. 30. The 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the patient is a breast-feeding mother who is advised to stop breast-feeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
31. 31. The 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the patient is a breast-feeding mother who is advised to stop breast-feeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
32. 32. The 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the patient is a breast-feeding mother who is advised to stop breast-feeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.