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WO2024160391A1 - Traitement de troubles mentaux - Google Patents

Traitement de troubles mentaux Download PDF

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Publication number
WO2024160391A1
WO2024160391A1 PCT/EP2023/076819 EP2023076819W WO2024160391A1 WO 2024160391 A1 WO2024160391 A1 WO 2024160391A1 EP 2023076819 W EP2023076819 W EP 2023076819W WO 2024160391 A1 WO2024160391 A1 WO 2024160391A1
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WO
WIPO (PCT)
Prior art keywords
dmt
meo
pharmaceutically acceptable
acceptable salt
breastfeeding
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Ceased
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PCT/EP2023/076819
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English (en)
Inventor
Theis Terwey
Conor Burke
Naoise GAFFNEY
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GH Research Ireland Ltd
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GH Research Ireland Ltd
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Filing date
Publication date
Priority claimed from PCT/EP2023/057885 external-priority patent/WO2023186837A1/fr
Application filed by GH Research Ireland Ltd filed Critical GH Research Ireland Ltd
Priority to IL322427A priority Critical patent/IL322427A/en
Priority to AU2023427992A priority patent/AU2023427992A1/en
Priority to CN202380094304.6A priority patent/CN120641095A/zh
Priority to KR1020257028947A priority patent/KR20250138805A/ko
Publication of WO2024160391A1 publication Critical patent/WO2024160391A1/fr
Priority to MX2025008749A priority patent/MX2025008749A/es
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient who is a mother, in particular a breastfeeding mother, diagnosed with a mental or nervous system disorder.
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • the mental disorder is amenable to treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the treatment also improves maternal functioning.
  • the invention moreover allows for treating the mental or nervous system disorder in a breastfeeding mother without substantial interruption of breastfeeding.
  • Mental or nervous system disorders in breastfeeding mothers can lead to a wide range of negative consequences for the affected mother, her infant(s) and her family.
  • women suffering from a mental or nervous system disorder may develop thoughts of self-harm or harming their child and they are at increased risk of suicide.
  • Mental or nervous system disorders may further lead to disruptions in the interactions between mother and child, exemplified by higher rates of disengaged behaviour and lower rates of visual and vocal communication between mother and child.
  • Evidence also suggests an association between mental or nervous system disorders a mother suffers from and child development, as illustrated by the fact that children of patients suffering from a mental or nervous system disorder may have a greater risk of impaired cognitive development.
  • a compounding factor is that for many medicaments, lactating women are advised to discontinue breastfeeding during the period in which they take the medicament and for some time thereafter as the medicament may be excreted in milk and expose the suckling child to a risk.
  • breastfeeding patients suffering from a mental or nervous system disorder may be confronted with a situation where a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.
  • Hallucinogens including psychedelics are chemical compounds, some naturally occurring, some synthetic, which are defined by their ability to induce in humans after consumption sensory distortions, such as changes in auditory and visual perception, as well as distortions of mood and cognition.
  • the term hallucinogen encompasses a rather broad group of psychoactive molecules with different modes of action. Some mental disorders have been suggested as in principle being amenable for treatment with psychoactive molecules, like psychedelics.
  • 5-methoxy-N,N-dimethyltrypta- mine 5-MeO-DMT.
  • TRD treatment resistant depression
  • an aim of the invention is in particular the provision of therapies which are more effective (i.e., a) larger percentage of patients experiencing a clinical response, b) a larger average clinical response, c) an earlier onset of the clinical response, and/or d) a more durable clinical response) than previously described therapies.
  • a still further aim of the current invention is to identify specific disease aspects and specific subgroups of disease aspects which benefit from such improved psychoactive therapies.
  • Still further aims of the invention are to improve maternal functioning in patients suffering from a mental or nervous system disorder, in particular in a breastfeeding mother diagnosed with a mental disorder.
  • the present invention provides 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a mother diagnosed with a mental or nervous system disorder, in particular a breastfeeding mother diagnosed with such a disorder.
  • 5-MeO-DMT 5-Methoxy-N,N-dimethyltryptamine
  • the disorder may be in particular a disorder characterized by depressive episodes, for example, Major Depressive Disorder (MDD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Anxiety Disorder, for example, Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobia, and Substance/Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain, Fibromyalgia, and Migraine; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; an Eating Disorder; Attention Deficit Hyperactivity Disorder
  • the patient may suffer from sleep disturbance.
  • the treatment allows for an improvement in maternal functioning.
  • the patient to be treated is in particular a breastfeeding mother.
  • the invention also allows for treating a breastfeeding mother without substantial interruption of breastfeeding.
  • the present invention also provides dose ranges and dosing regimen useful for the treatments indicated above.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous administration.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a peak psychedelic experience.
  • a dosage of about 1 mg to about 10 mg 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt may be administered.
  • 5- MeO-DMT refers to the free base 5-MeO-DMT.
  • pharmaceutically acceptable salts of 5-MeO-DMT may also be used.
  • Such salts are in particular acid addition salts, wherein the acid may be selected from, for instance, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and triflic acid.
  • a preferred example is the hydrobromide salt.
  • the appropriate weight amount of a salt to be administered can be calculated from the weight amount of the free base, assuming that equimolar amounts are used.
  • a "patient" to be treated is a mother having a child, typically of 18 months or younger, in particular of 12 months or younger, who is diagnosed with a mental or nervous system disorder by a licensed professional in accordance with accepted medical practice.
  • Diagnosis of a mental disorder or a nervous system disorder can, for instance, be in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition
  • the criteria may be modified or supplemented to better define patients or patient groups particularly benefiting from a treatment according to the invention.
  • the diagnosis will in any event be by a physician or a psychologist. It is not sufficient that the human subject himself considers that he is suffering from the disorder.
  • treating shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms of the disease or eliminate the disease, condition, or disorder.
  • the patient may suffer from treatment resistant disease.
  • Treatment resistance means that the patient had no adequate improvement after at least two adequate courses of therapy.
  • the patient in particular had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy; for instance, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy.
  • the at least two prior courses of treatment were in particular administered in the current episode of the disease, for instance, if the patient suffers from a disorder characterized by depressive episodes, in the current episode of depression.
  • suicidal ideation refers to thinking about, considering, or planning for suicide.
  • the presence of suicidal ideation in a patient will be diagnosed by a physician or a psychologist, using established protocols and methods for diagnosing suicidality. It is generally not sufficient that the patient himself considers that he is suffering from suicidal ideation. In some situations, a patient experiencing suicidal ideation will be at imminent risk of committing suicide, or will be considered to have 'intent to act.'
  • the term "therapeutically effective amount” shall mean the amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of the signs and/or symptoms of the disease, condition or disorder being treated.
  • “Clinical response” includes, but is not limited to, improvements on rating scales
  • CGI Clinical Global Impression
  • the CGI rating scales were developed to provide a brief, stand-alone assessment of the clinician’s view of the patient’s global functioning prior to and after a treatment (Busner, J. and Tagrum, S. D., 2007.
  • the CGI-S can be used to assess treatment success by comparing scores before and after treatment.
  • CGI-I CGI-Improvement
  • SGI Subject Global Impression
  • CGI-I Clinical Global Impressions scale
  • the severity of a condition as well as changes of the severity can further be assessed rating scales applicable for the particular mental or nervous system disorder the patient suffers from.
  • Maternal functioning may be assessed using the Barkin Index of Maternal Functioning (BIMF).
  • BIMF Barkin Index of Maternal Functioning
  • a rational modification of such endpoint e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration may be applied.
  • the term “administration” shall mean the introduction of an amount, which may be a predetermined amount, of active compound or pharmaceutical ingredient into a patient via any route.
  • the active compound is administered by intravenous administration, by intramuscular administration or by subcutaneous administration.
  • dose and “dosage” and “dosage amount” shall mean the amount of active compound or pharmaceutical ingredient which is administered to a patient in an individual administration.
  • dose regimen (or “dosing regimen") shall mean a defined sequence of one or more individual administrations.
  • the mental and nervous system disorders to be treated according to the invention have in common that they are associated with one or more symptoms from the symptom clusters discussed below, which include sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal and negative thinking.
  • the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5- MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient who is a breastfeeding mother diagnosed with a mental or nervous system disorder.
  • 5- MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • the mental or nervous system disorder is amenable to treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. It is in particular major depressive disorder, persistent depressive disorder, bipolar disorder, anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder or psychoactive substance abuse.
  • the mental disorder is major depressive disorder.
  • the mental disorder is Postpartum depression (PPD), a complex mix of physical, emotional, and behavioral changes that happen in some women after giving birth.
  • PPD is also known as major depressive disorder with peripartum onset.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
  • MDD major depressive disorder
  • the mental disorder is bipolar disorder, such as bipolar II disorder.
  • the patient diagnosed with bipolar disorder in particular suffers from a current major depressive episode.
  • Various aspects of bipolar disorder such as sleep disturbance, 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 detachment (anhedonia, emotional withdrawal and affective flattening) can be improved.
  • Further aspects of the disease which can be improved include suicidal ideation and mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation). The improvements that can be achieved are reflected on clinically relevant scales.
  • Scales for the assessment of mental or nervous system disorders which may be used according to the invention include those known in the art for diagnosis and/or monitoring the mental or nervous system disorders discussed in more detail below.
  • Treatment outcome is assessed by using one or more indices or scales at one or more time points after completion of a treatment course.
  • the assessment can be carried out after the acute psychedelic experience has subsided.
  • An appropriate point in time for an early assessment is generally about 2 to 3 hours after the last administration.
  • An early assessment can generally be carried out, for instance, about 2 hours or about 3 hours after the last administration.
  • An assessment of an effect on sleep disturbance or an effect on a mental or nervous system disorder related to an effect on sleep disturbance can, however, be carried out at the earliest on the day after the treatment (/.e., on day 1) so that the treated patient had the opportunity to sleep for at least one night.
  • an assessment at day 1 or on day 1 means an assessment on the day following the administration.
  • the assessment will be carried out not earlier than 12 hours after the last administration and in any event not earlier than one night after the last administration and not later than 36 hours after the last administration.
  • the assessment can be carried out after about 24 hours.
  • An assessment at day 7 or on day 7 means an assessment on the seventh day following the administration (the day of administration is day 0). Analogous definitions apply for other assessment timings measured in days.
  • a clinical response for instance, using one of the scales to assess severity of a mental disorder or a nervous system disorder, at an early timepoint after drug administration (e.g. at 2 hours) based on endpoints which have been developed for a longer recall period (e.g. normally 7 days for the MADRS), a rational modification of such endpoint (e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied.
  • a rational modification of such endpoint e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration
  • the Active Agent is the Active Agent
  • a carefully chosen hallucinogen may allow continuing breastfeeding without substantial interruption in case of treatment of a breastfeeding mother suffering from a mental or nervous system disorder.
  • hallucinogens entails compounds which bind to the 5-hydroxytryptamine (5-HT) receptors, which are also referred to as serotonin receptors (described are 7 families 5-HT1 to 5-HT7 with several subtypes). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT).
  • serotonergic agents are often referred to as "psychedelics", which emphasizes their predominant ability to induce qualitatively altered states of consciousness such as euphoria, trance, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences, while other effects such as sedation, narcosis, or excessive stimulation are only minimal.
  • serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamine class being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.
  • the various serotonergic psychedelics have different binding affinity and activation potency for various serotonin receptors, particularly 5-HT1A, 5-HT2A, and 5-HT2C, and their activity may also be modulated by interaction with other targets such as monoamine transporters and trace amine-associated receptors.
  • Lake et al. (Lake, C. R., Stirba, A. L., Kinneman, R. E. Jr, Carlson, B., Holloway, H. C., 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) report about a patient who suffered a manic attack after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication, which resolved but were followed in about 3 weeks by a typical manic episode of psychotic magnitude. Hendin and Penn (Hendin, H.M., Penn, A. D., 2021.
  • the compound administered in order to avoid the induction of mania or hypomania or at least reduce the risk of induction of mania or hypomania, the compound administered must be appropriately chosen and preferably is administered in a particular dosing regimen.
  • 5-methoxy-N,N-dimethyltryptamine 5-MeO-DMT
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist, acting at both the 5-HT 1 A and the 5-HT2A receptor, with higher affinity for the 5-HT 1 A receptor subtype compared to other classical psychedelics.
  • Inhibition constants Kj values as further detailed on the example section below for psilocin (the dephosphorylated from of psilocybin which is formed after uptake of psilocybin), DMT and 5-MeO-DMT are 48, 38 and 1.80 nM, respectively, at 5-HT1 A receptors located in the hippocampus of post-mortem human brain.
  • 5-MeO-DMT exhibits high affinity and psilocin and DMT exhibit moderate affinity for 5-HT1A receptors.
  • Inhibition constants (Kj values) for psilocin, DMT and 5-MeO-DMT are 37, 117 and 122 nM, respectively, at 5-HT2A receptors located in the frontal cortex of post-mortem human brain. Therefore, psilocin exhibits moderate/strong affinity and DMT and 5-MeO-DMT exhibit comparatively weak affinity for 5-HT2A receptors.
  • 5-MeO-DMT displays an enhanced affinity for the 5-HT1 A receptor, where it acts as a potent agonist.
  • 5-HT1A binding plays a much bigger role in the overall effect of 5-MeO-DMT relative to 5-HT2A binding compared to the other two compounds. It has been reported that 5-HT1A agonism reduces impulsivity and aggression, whereas 5-HT2A agonism can result in short-term increases in these same traits.
  • dopamine system has been implicated in contributing to mania, with increased dopamine drive being linked to mania.
  • LSD, psilocybin and DMT all display increased affinity for a variety of dopamine receptors relative to 5-MeO-DMT
  • 5-MeO-DMT can be administered to patients, preferably using dosing schemes as described herein, without a significant risk of inducing mania or hypomania in a patient suffering from a mental or nervous system disorder, including a disorder characterized by depressive episodes, for example, Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; a Psychotic Disorder, such as Schizophrenia; or a personality disorder, such as Schizotypal Personality Disorder.
  • MDD Major Depressive Disorder
  • PPD Postpartum Depression
  • BD Persistent Depressive Disorder
  • BD Seasonal Affective Disorder and Bipolar Disorder
  • BD Bipolar I Disorder and Bipolar II Disorder
  • a Psychotic Disorder such as Schizophrenia
  • a personality disorder such as Schizotypal Personality Disorder.
  • the patient suffering from such a mental or nervous system disorder, treated according to the invention does not
  • the inventors’ approach of sequential up-titration of 5-MeO-DMT significantly reduces the risk of excessive dose administration with its potential for attendant adverse events.
  • 5-MeO-DMT can induce peak experiences, i.e., experiences characterized by an emotional perspective shift, which is described as "loss of ego” which often culminates in an overwhelming sense of "oneness with the universe", more rapidly than other psychedelics and has a short duration of acute psychedelic effects (5 to 30 minutes after intravenous injection compared with several hours for e.g. oral psilocybin and oral LSD).
  • These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile which can be explained by specific alterations of Resting State Network (RSN) activity under 5-MeO-DMT treatment.
  • RSN Resting State Network
  • 5-MeO-DMT is a 5-HT7 receptor agonist showing high affinity towards the receptor.
  • the inventors determined, using recombinant human 5-HT7 receptor, [ 3 H]LSD as a radio ligand and serotonin to estimate non-specific binding, a Kj of 2.3 nM.
  • 5-MeO-DMT also interacts with the 5-HT7 receptor.
  • 5-MeO-DMT act as an agonist on this receptor and shows a high (nanomolar) binding affinity.
  • the 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation. It is, among other things, associated with central processes such as learning and memory, with sleep regulation and circadian rhythm and with nociception.
  • the 5-HT7 receptor is in particular expressed in the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the 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 will result in disease states, in particular disease states involving sleep disturbance. In patients suffering from sleep disturbance resting state functional connectivity analysis reveals alterations in functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.
  • the expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of the receptor in regulation of sleep/wake cycles.
  • the inventors consider that this allows treatment of patients suffering from sleep disturbance by 5-MeO-DMT which acts on the receptor.
  • the inventors consider that binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT, which involve functional connectivity "resets" of networks and neuroplasticity effects, contributes to the beneficial effects of 5- MeO-DMT in the treatment of patients suffering from sleep disturbance.
  • the inventors further consider that binding of 5-MeO-DMT to the 5-HT7 receptor as well as to the 5-HT1A receptor as two mediators of effects exerted by 5-MeO-DMT, which include functional connectivity "resets" of networks and neuroplasticity effects, allows achieving beneficial effects also in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or so- cial/emotional withdrawal. This is supported by the clinical results demonstrated in studies referred to herein.
  • 5-MeO-DMT is mainly inactivated through a deamination pathway mediated by monoamine oxidase A, and it is O-demethylated by cytochrome P4502D6 (CYP2D6) enzyme.
  • the inventors investigated 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.
  • 5-MeO-DMT offers various characteristics that renders it an attractive treatment for PPD.
  • it is a rapid-acting agent (in a 5-MeO-DMT-TRD trial, 5/8 patients with TRD achieved a remission within 2h after dosing, and 8/8 patients achieved a remission on day 1 , with 7/8 patients maintaining their remission at Day 7).
  • 5-MeO-DMT to treat PPD patients, not only can a rapid improvement of depressive symptoms be achieved, but also a rapid improvement of maternal functioning.
  • 5-MeO-DMT is administered during a single-day treatment session, with optional infrequent redosing, thus differentiating it from SSRIs, which require a chronic daily dosing regimen associated with low compliance, and in the case of brexanolone, requiring protracted infusions and hospital admission.
  • the present invention thus also addresses compliance and patient convenience.
  • isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof can also be used.
  • isotopic variants is also contemplated.
  • Deuterated forms of 5-MeO-DMT are forms having a higher deuterium content than expected based on the natural abundance of this isotope.
  • Deuterated forms of 5-MeO-DMT are in particular forms wherein deuterium has been introduced at one or more defined hydrogen positions.
  • Examples of deuterated forms of 5-MeO-DMT include, without limitation, 1-deuterio-2- (5-methoxy-1 H-indol-3-yl)-N,N-dimethylethanamine, 1 ,1-dideuterio-2-(5-methoxy-1 H-in- dol-3-yl)-N,N-dimethylethanamine, 1 ,1 ,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)- N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1 H-indol-3-yl]eth- anamine.
  • mixtures of deuterated forms of 5-MeO-DMT mixtures of one or more deuterated form with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixture of such salts as well as mixtures of salts of deuterated and non-deuterated 5-MeO-DMT can also be used.
  • deuterated 5-MeO-DMT and salts of deuterated 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-deuterated forms.
  • prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used.
  • Such prodrugs of 5-MeO-DMT can be metabol- ically converted to 5-MeO-DMT.
  • this when reference is made to the use of 5-MeO- DMT or a pharmaceutically acceptable salt thereof, this can be replaced by a 5-MeO- DMT prodrug or a salt thereof.
  • the hydrogen in position 1 of the indole moiety is substituted by an organic moiety which can be split off after administration.
  • Suitable organic moieties are -C(O)OR 1 , -C(O)R 2 , -CH(R 3 )OR 4 , - C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , - CH(R 3 )OC(O)OR 4 , wherein each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.
  • organic moieties are -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , wherein R 1 , R 3 , and R 4 are defined as above.
  • Prodrugs especially those of the above structure, can also be used on the form of pharmaceutically acceptable salts.
  • prodrugs are 5-MeO-DMT carboxy-isopropyl valinate, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2- methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1 H-indole-1-carboxylate di-trifluoro- acetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-rnethoxy-1 H-in- dol-1-yl)methyl pivalate).
  • the T ma x value of the metabolite 5-MeO-DMT as measured in male Sprague-Dawley (SD) rats following oral dosing of the prodrug at 10 mg/kg is preferably 1 hour or less, more preferably 0.7 hours or less and in particular 0.5 hours or less.
  • prodrugs of 5-MeO-DMT and salts of prodrugs of 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-prodrug forms.
  • the therapeutically effective amount of 5-MeO-DMT is administered by intravenous administration, by intramuscular administration or by subcutaneous administration. Administration via these routes can assure a rapid onset of action.
  • a most preferred route of administration is administration via the intravenous route, i.e. by intravenous injection.
  • 5-MeO-DMT can be employed as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations being known in the art.
  • the present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes) and appropriate routes of administration.
  • the invention is in part based on the inventors' conclusion that the occurrence of a peak psychedelic experience during the acute phase after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is driving its therapeutic benefit in patients as defined herein, who is diagnosed with a disorder as defined herein, including a treatmentresistant form of this disorder, and including this disorder associated with suicidal ideation, in particular one or more of the aspects defined above, either in a causal relationship or at least as a surrogate behavioral marker for the underlying unknown therapeutic mechanism.
  • the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of relevant tolerance (i.e., the absence of diminished or no psychedelic effects after re-administration), as a basis for enabling a dosing regimen with frequent re-administrations (such as more than once daily, or daily), which are designed to increase the rate of occurrence of peak experiences, thereby increasing the therapeutic benefit.
  • Such repeat administrations within short time also allow an intraindividual doseoptimization which reduces the risk of overdosing, which may otherwise lead to somatic side effects, such as the serotonin syndrome, negative psychic reactions, such as flashbacks of the experience at later timepoints, induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state (so- called "white-outs").
  • somatic side effects such as the serotonin syndrome
  • negative psychic reactions such as flashbacks of the experience at later timepoints
  • induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state so- called "white-outs”
  • a patient as defined herein who is diagnosed with a disorder as defined herein, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, who is treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the 5-MeO-DMT is administered as a monotherapy, i.e., the patient does not receive any other treatment for diagnosed disorder.
  • the dosage amount of 5-MeO-DMT administered to a patient, as defined herein, who is diagnosed with a disorder as defined herein, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, is in the range of about 1 mg to about 10 mg, or any amount of range therein and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, which weight amount can be calculated from the stated weight amounts of the 5-MeO-DMT free base, assuming that equimolar amounts are used.
  • Useful specific amounts of 5-MeO-DMT are e.g.
  • the improved methods for the treatment of a patient, as defined herein, who is diagnosed with a disorder as defined herein, including a treatmentresistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the occurrence of a clinical response not later than about 2 hours after administration of 5-MeO-DMT.
  • the improved methods for the treatment of a patient, as defined herein, who is diagnosed with a disorder as defined herein, including a treatmentresistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the persistence of a clinical response, including a clinical response which occurred not 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, more preferably until at least about 28 days after the last administration of 5-MeO-DMT.
  • the improved methods for the treatment of a patient, as defined herein, who is diagnosed with a disorder as defined herein, including a treatmentresistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the administration of more than a single dose of 5-MeO-DMT.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with not less than about 1 hour and not more than about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each of the administrations and in each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 10 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects.
  • the dosage amount for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg to the dosage amount of the prior administration. For example, if the dosage amount of the first administration was 1 mg and the dosage amount increase is 3 mg, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be 4 mg. Preferably, the dosage amount for the third administration will be 7 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4 mg to about 6 mg for the second administration, and from about 7 mg to about 9 mg for the third administration.
  • Useful specific amounts for the first, second and third administration are e.g. about 2 mg, about 5 mg, and about 8 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration, and from about 2.5 mg to about 3.5 mg for the third administration.
  • Useful specific amounts for the first, second and third administration are e.g. about
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1.5 mg to about
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2.5 mg to about
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 3 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4.5 mg to about 5.5 mg for the second administration, and from about 7 mg to about 8 mg for the third administration.
  • Useful specific amounts for the first, second and third administration are e.g. about 2.5 mg, about 5 mg, and about 7.5 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of the first treatment block, and then increases with each subsequent administration within that first treatment block until the earlier of 10 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects, with that highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dosage in the first treatment block was 8 mg because the patient experienced a peak psychedelic experience at that dose, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block, and from about 7 mg to about 9 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 2 mg, about 5 mg, and about 8 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block, and from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 1 mg, about 2 mg, and about 3 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 3 mg to about 5 mg for the second administration of the first treatment block, and from about 5 mg to about 7 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 2 mg, about 4 mg, and about 6 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 4 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block, and from about 6 mg to about 8 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 3 mg, about 5 mg, and about 7 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 1.5 mg to about 3.5 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block, and from about 6.5 mg to about 8.5 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g.
  • a pharmaceutically acceptable salt of 5-MeO-DMT is preferably used in all of the above dosing regimen, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.
  • 5-MeO-DMT is preferably not administered together with a MAO inhibitor.
  • the occurrence of a "peak psychedelic experience" in a patient can be identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30- item revised Mystical Experience Questionnaire (M EQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).
  • the occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018; 8:974).
  • OBN Oceanic Boundlessness
  • ASC Altered States of Consciousness
  • the occurrence of a "peak psychedelic experience" in a patient is preferably identified through achievement of a score of at least 75 in the Peak Experience Scale (PES) Total Score, also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ), which averages answers scored by the patient from 0 to 100 for the following three questions: 1. How intense was the experience; 2. To what extent did you lose control; 3. How profound (i.e. deep and significant) was the experience?
  • PES Peak Experience Scale
  • PPEQ Peak Psychedelic Experience Questionnaire
  • Non-REM sleep can be divided into four stages (l-IV). These non-REM stages correspond to an increasing depth of sleep.
  • Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night.
  • non-REM sleep is deeper and occupies a disproportionately large amount of time, particularly within the first cycle of sleep.
  • non- REM sleep becomes shallow and more of each cycle is allocated to REM sleep.
  • Normal healthy sleep consists of different phases as outlined above that proceed in successive, tightly regulated order through the night.
  • Sleep disturbance refers to conditions, whether idiopathic or occurring in the context of a medical condition such as for example a mental disorder or a nervous system disorder, that affect sleep quality, timing, or duration. It impacts a person’s ability to properly function while the person is awake.
  • sleep disturbances encompass disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleepwake schedule (circadian rhythm disorders), dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia), disorders characterized by respiratory disturbance during sleep (sleep-related breathing disorders) and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).
  • Insomnia is a sleep disturbance where people have difficulty falling or staying asleep. People with insomnia have difficulty falling asleep; wake up often during the night and have trouble going back to sleep; wake up too early in the morning; have unrefreshing sleep; and/or have at least one daytime problem such as fatigue, sleepiness, problems with mood, concentration, accidents at work or while driving, etc. due to poor sleep.
  • Hypersomnia is characterized by excessive daytime sleepiness, and/or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomnia patients. It is a difficulty transitioning from sleep to wake. Individuals experiencing sleep drunkenness report waking with confusion, disorientation, slowness and repeated returns to sleep.
  • Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances due to alterations of the individual’s internal circadian rhythm or due to misalignments between their circadian rhythm and their desired or required work or social schedule. This dyssynchrony may be transient or persistent.
  • the ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during the desired waking state is impaired, and temporary opportunities to revert to a regular sleep schedule are unsuccessful.
  • Parasomnia designates various forms of sleep disturbance characterized by abnormal behavioural or physiological activity (such as sleepwalking or nightmares) that people experience prior to falling asleep, while asleep, or during the arousal period between sleep and wakefulness. There are considerable variations in terms of characteristics, severity, and frequency. Parasomnia may compromise the quality of sleep.
  • Sleep-related breathing disorders are characterized by abnormal and difficult respiration during sleep. Respiration is a complex process that relies heavily on the coordinated action of the muscles of respiration and the (control center in the) brain.
  • One form of a sleep-related breathing disorder is central sleep apnoea. It occurs when the brain stops sending signals that control breathing, for instance, based on an underlying health condition.
  • Central sleep apnoea has a potentially serious impact on sleep and the balance of oxygen and carbon dioxide in the blood.
  • the reduction of airflow leads to intermittent hypoxia which in leads to sleep fragmentation due to microarousals or awakenings. A consequence can be excessive daytime sleepiness.
  • RLS restless leg syndrome
  • PLMD periodic limb movement disorder
  • Sleep disturbance may also interfere with cognitive function and lead to memory impairment.
  • a subject who is deprived of sleep may experience difficulty making decisions, irritability, have problems with performance, and may have slower reaction times. Sleep loss can also adversely affect life by contributing to the development of obesity, diabetes, and heart disease.
  • Treatment of sleep disorders varies depending on the type and underlying cause. Maintenance of good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered as first-line treatment. If not successful, treatment also involves pharmacotherapy or psychotherapy.
  • sleep disturbance is frequently associated with mental disorders, such as depression.
  • treatment of depression does not necessarily lead to an improvement of the concomitant sleep disturbances.
  • antidepressants While most antidepressants have been proven to influence the sleep architecture, some classes of antidepressants improve sleep, but others may cause sleep impairment.
  • sleep disturbance may be considered a condition deserving treatment independent of any other condition, disorder or symptom an individual may suffer from
  • several mental disorders and nervous system disorders are associated with sleep disturbance.
  • the relationship between sleep and a mental or nervous system disorder is often bidirectional. Not only can mental or nervous system disorders have a negative impact on a healthy sleep pattern but sleep disturbance can also be a contributing factor to the onset, progression, and prognosis of mental health or nervous system disorders.
  • the treatment according to the invention reduces or eliminates sleep disturbance and preferably also improves the associated mental disorder or nervous system disorder.
  • Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of awakenings throughout the night.
  • the quantitative metrics may be measured using objective methods, including polysomnography, actigraphy, and the determination of sleep latency, or by way of selfreported measures (questionnaires).
  • Polysomnography is a technique requiring that a patient is monitored overnight at a specialized clinic.
  • a variety of functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body positioning and movements, snoring, and heart rate.
  • An actimetry sensor is worn to measure motor activity, which is recorded continually and used to assess sleep-wake cycles. This technique allows the patient to continue normal routines while the required data are being recorded in natural sleep environment.
  • Sleep latency can be measured by the multiple sleep latency test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep across a multiplicity of test naps. An average sleep latency of approximately 10 minutes is considered to be normal; less than eight minutes is indicative of sleep disturbance (excessive daytime sleepiness).
  • MSLT multiple sleep latency test
  • Sleep-rating questionnaires capture ratings of components of sleep quality, such as perceptions of sleep depth, rousing difficulties, and restfulness after sleep, in addition to other factors that could affect sleep quality, such as comorbid conditions and medication use.
  • the evaluation of the qualitative aspects of sleep experience is important, as sleep complaints can often persist despite normal values for quantitative measures of sleep.
  • Questionnaires not only facilitate a quick and accurate assessment of a complex clinical problem, but they are potentially also helpful for tracking a patient's progress.
  • indexes include examples of questionnaires to assess sleep in general and questionnaires to assess in particular insomnia, hypersomnia, circadian rhythm disorders and parasomnia, respectively.
  • the invention is, however, not limited to the use of a particular index or questionnaire.
  • recall periods recall windows
  • the recall period can be modified so that the scores obtained reflect a period after treatment.
  • Questionnaires specifically discussed herein to assess effects of a treatment on sleep in patients suffering from specific conditions rely on a recall period that does not start earlier than the time point when acute psychedelic experiences have subsided after the last administration. To meet this criterion, the normally applied recall period is modified if necessary.
  • Sleep quality in general can be assessed, for instance, with the Sleep-50 questionnaire.
  • the SLEEP-50 questionnaire consists of 50 items designed to screen for a variety of sleep disorders in the general population.
  • the scale consists of nine subscales, reflecting some of the most common disorders and complaints related to sleep and the factors required for diagnosis such as sleep apnoea, insomnia, narcolepsy, restless legs/peri- odic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors influencing sleep, and the impact of sleep complaints on daily functioning.
  • respondents are provided with a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate the extent to which the statement has matched their experience over the previous month or another appropriate recall window.
  • the specific subscale e.g., insomnia
  • respondents must also meet a cut-off of at least 3 or 4 (“rather much” or “very much”, respectively) on the subscale evaluating the impact of sleep complaints on daily functioning (Spoormaker et al., Initial validation of the SLEEP- 50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).
  • Treatment success is indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value.
  • a common questionnaire assessing sleep disturbance is the Pittsburgh Sleep Quality Index.
  • Other instruments are the insomnia severity index, the Espie sleep disturbance questionnaire and the Patient Reported Outcomes Measurement Information System (PROMIS®) Sleep Disturbance.
  • PROMIS® Patient Reported Outcomes Measurement Information System
  • the Pittsburgh Sleep Quality Index assesses overall sleep quality and disturbances.
  • the PSQI is a self-rated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window.
  • the 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction.
  • the seven component scores are then summed to yield one global score, with a range of 0-21 points, "0" indicating no difficulty and "21" indicating severe difficulties in all areas.
  • a global score cut-off of 5 distinguishes poor from good sleepers.
  • a global score > 5 indicates that a patient is having severe difficulties in at least two areas, or moderate difficulties in more than three areas.
  • treatment success is indicated (i) by a decrease of the score, preferably (ii) by a decrease to 5 or below.
  • Treatment success is indicated (i) by a decrease of the score, for instance, by > 7 points, in particular > 8 point; preferably (ii) by a decrease to below the cut-off value for clinically significant insomnia.
  • the Espie sleep disturbance questionnaire evaluates subjective experiences of insomnia. With ratings on restlessness/agitation, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ is concerned specifically with beliefs about the sources of sleep issues. Respondents use a five-point scale to indicate how often certain statements about insomnia are representative of their experience. 1 means “never true,” while 5 means “very often true.” Higher scores are indicative of more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc. cit. ;).
  • Treatment success is indicated by a decrease of the score.
  • the Patient- Reported Outcomes Information System (PROMIS)® Sleep Disturbance instrument is a universal measure to evaluate sleep disturbances.
  • the instrument is available as a long form and 4 different short forms (e.g., 4-, 6-, and 8- items) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulties related to getting and staying asleep over a 7-day period.
  • Each item on the measure is rated on a 5-point scale.
  • the raw scores on the items are summed to obtain a total raw score. Total raw scores are then converted into a standardized T-score using conversion tables.
  • Treatment success is indicated by a decrease of the T-score.
  • Hypersomnia or hypersomnolence can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity scale.
  • the Epworth Sleepiness Scale evaluates overall daytime sleepiness.
  • the questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations representing a moment of relative inactivity, such as a nap in the afternoon or sitting in a car stopped in traffic.
  • a scale of 0-3 with 0 meaning "would never doze” and 3 meaning "high chance of dozing"
  • respondents rate their likelihood of falling asleep. Scoring ranges from 0-24; the higher the score, the higher the severity of daytime sleepiness.
  • a cut-off score of 10 identifies daytime sleepiness at a potentially clinical level (A. Shahid et al., loc. cit.).
  • Treatment success is indicated by a decrease of the score.
  • PDSS Paris Arousal Disorders Severity Scale
  • Treatment success is indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value.
  • a common questionnaire that assesses sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc. cit. ;). An appropriate recall period can also be chosen.
  • Treatment success is indicated by a decrease of the score.
  • a common questionnaire that assesses sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale.
  • the 10-item questionnaire asks respondents to use Likert-type ratings to indicate how acutely the disorder has affected them over the course of the past week. Questions can be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep issues, disturbances in daily functioning, and resultant changes in mood.
  • Each of the ten questions requires respondents to rate their experiences with RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores can range from 0 to 40.
  • the instrument may be suitable for a variety of research and clinical purposes, including screening and assessment of treatment outcomes. (A. Shahid et al., loc. cit.).
  • Treatment response can be assessed by a decrease of the score.
  • resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSN), which are a set of spatially distinct brain regions that show coordinated activity in the absence of any explicit cognitive task (i.e. , at rest).
  • the observed patterns, characterizing a network of brain regions with coherent patterns of signal variation, are called resting-state networks (RSN).
  • RSN resting-state networks
  • Different resting state networks have been identified and named mostly based on spatial similarity between the resting state networks and activation patterns seen in task fMRI experiments.
  • Resting-state fMRI can therefore 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 system.
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised 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).
  • the DMN is deactivated during tasks and activated at rest. It is involved in multiple cognitive processes such as higher cognition, emotion, and interoception.
  • DMN its overall activity level decreases. Given the importance of the DMN for sleep physiology, altered activity of the DMN is of particular relevance in the context of sleep disturbance.
  • Compromised resting state networks can also be found in mental disorders or nervous system disorders as further discussed herein.
  • Resting state networks involved in sleep disturbance are also affected by mental or nervous system conditions which are a consequence of certain medical health conditions.
  • insomnia patients dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is implicated in the detection and integration of emotional and sensory stimuli. Studies have suggested that these networks contain critical regions integrating emotional and bodily states, and the dysfunctional connectivity within and/or between these networks and other brain areas may underlie the vigilance, subjective distress, and poor sleep continuity of patients.
  • DNN default mode network
  • salience network which is implicated in the detection and integration of emotional and sensory stimuli.
  • these networks contain critical regions integrating emotional and bodily states, and the dysfunctional connectivity within and/or between these networks and other brain areas may underlie the vigilance, subjective distress, and poor sleep continuity of patients.
  • the default mode network is affected.
  • distinct DMN hubs - the precuneus and medial prefrontal cortex - demonstrate significant changes, and functional connectivity in the DMN correlates with self- reported sleepiness severity.
  • rhythm disorders contributes to resting-state functional changes in the cerebellum, involved in sleep regulation, and cognitive functions such as responsiveness and alertness.
  • functional connectivity of the DMN is fundamentally different in early and late circadian phenotypes.
  • circadian rhythm disorders can lead to changes in brain functional connectivity. Changes in resting state brain functional connectivity have been reported in various diseases with circadian rhythm disorders.
  • the precuneus is involved in the analysis and integration of visual, audio, and somes- thetic information and the monitoring of movements.
  • the precuneus is a subregion of the DMN. Thus, in patients with parasomnias the default mode network is affected.
  • Sleep-related movement disorders such as for example periodic limb movements during sleep are reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Also, activity in the cerebellum and thalamus, with additional activation in the red nuclei and brainstem can be observed.
  • idiopathic sleep disturbance as well as sleep disturbance in patients suffering from mental disorders or nervous system disorders can be treated.
  • a treatment of sleep disturbance according to the invention leads to an improvement of the condition with which the sleep disturbance is associated.
  • resting state networks involved in sleep disturbance are also involved in the conditions listed above.
  • 5-MeO-DMT has the ability to disrupt established functional connectivity patterns of resting state networks. This disruption leads to a reset of the pathological ill-connected brain connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • 5-MeO-DMT in particular fosters the structural and functional plasticity of synapses, /.e., of sites where neurons connect and communicate with each other.
  • 5-MeO-DMT modulates morphogenesis and maturation of dendritic spines so that the formation of new synaptic connections is initiated. These new connections will be strengthened or weakened or even be eliminated, dependent on activity.
  • New synapses ultimately formed will in turn influence the activity patterns of the neurons.
  • the inventors conclude that such reciprocal structural and functional modifications contribute to a proper establishment of networks and the persistence of effects after administration of 5-MeO-DMT.
  • 5-MeO-DMT interacts, among others, with 5-HT receptors.
  • 5-HT receptors receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5- HT), are found throughout the central and the peripheral nervous system. A wide range of physiological and pathological functions are mediated via these receptors.
  • 5-HT receptors which can be further separated into several subtypes are expressed.
  • the various types and subtypes show distinct spatial distributions.
  • 5-MeO-DMT interacts with several of the 5-HT receptors. These receptors are involved in mediating effects of 5-MeO-DMT on resting state networks and neuronal plasticity. Besides 5-HT1A and 5-HT2A discussed above, 5-MeO-DMT also interacts with the 5- HT7 receptor. 5-MeO-DMT act as an agonist on this receptor and shows a high (nanomolar) binding affinity.
  • the 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation. It is, among other things, associated with central processes such as learning and memory, with sleep regulation and circadian rhythm and with nociception.
  • the 5-HT7 receptor is in particular expressed in the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the 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 will result in disease states, in particular disease states involving sleep disturbance. In patients suffering from sleep disturbance resting state functional connectivity analysis reveals alterations in functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.
  • the expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of the receptor in regulation of sleep/wake cycles.
  • the inventors consider that this allows treatment of patients suffering from sleep disturbance by 5-MeO-DMT which acts on the receptor.
  • the inventors consider that binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT, which involve functional connectivity "resets" of networks and neuroplasticity effects, contributes to the beneficial effects of 5- MeO-DMT in the treatment of patients suffering from sleep disturbance.
  • the inventors further consider that binding of 5-MeO-DMT to the 5-HT7 receptor as well as to the 5-HT1A receptor as two mediators of effects exerted by 5-MeO-DMT, which include functional connectivity "resets" of networks and neuroplasticity effects, allows achieving beneficial effects also in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or so- cial/emotional withdrawal. This is supported by the clinical results demonstrated in studies referred to herein. A treatment according to the invention will lead to an improvement of the sleep disturbance and, if the patient treated suffers from a mental disorder or a nervous system disorder, also of that disorder.
  • the MADRS item "reduced sleep” represents the experience of reduced duration or depth of sleep compared to the subject's own normal pattern when well.
  • a score of 0 is assigned when the subject sleeps as usual.
  • a score of 2 reflects slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
  • a score of 4 means that sleep is reduced or broken by at least two hours.
  • a score of 6 means less than two or three hours sleep.
  • the aggregated score for the MADRS item "reduced sleep" across all 8 patients was 25 at base line.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 9 which corresponds to an improvement of 16 points or 64%.
  • the aggregated score for the MADRS item "reduced sleep" across all 4 patients was 12 at base line. At day 1 after treatment, it was reduced to 10 which corresponds to an improvement of 2 points or 17%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 6 points or 50%.
  • the score of the scale item that is of particular relevance to sleep disturbance is markedly improved.
  • 5-MeO-DMT can be used to treat sleep disturbance, in particular patients suffering from a mental disorder or a nervous system disorder.
  • Cognition includes the skills needed for thinking, remembering, paying attention, and solving problems. Loss or decline of these skills leads to cognitive dysfunction, a term used herein to refer to a deficit in, or an impairment of, any domain of cognition. Cognitive dysfunction may be one of the manifestations of a patient's underlying condition.
  • the DSM-5 defines six key domains of cognitive function, namely complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.
  • Cognitive dysfunction can impact one or more of those domains.
  • cognitive abilities are highly interrelated, and it is not unusual that more than one domain is affected.
  • the domain complex attention has the subdomains sustained attention (commonly referred to as 'concentration' or 'focus'), divided attention, selective attention, and processing speed.
  • Cognitive control or executive function is intrinsically attentional. Also, perception, and decision-making are profoundly influenced by attention abilities.
  • Cognitive dysfunction which term herein means an acquired condition and thus represents a decline from a previously attained level of functioning, can be associated with various processes.
  • Cognitive dysfunction furthermore occurs in disorders showing symptoms characteristic of a neurocognitive disorder that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any aetiology-related disorder.
  • Cognitive dysfunction may take the form of a neurocognitive disorder.
  • Cognitive dysfunction can be evaluated by questionnaires or by neuropsychological assessments.
  • Questionnaires assess the mental status of a patient based on observations made by the patient himself, caregivers or the clinician administering the questionnaire.
  • Questionnaires used to assess whether a patient suffers from a particular mental or nervous system disorder may comprise items related to cognitive function.
  • a neuropsychological assessment is a process by which a person’s cognitive, psycho- logical/emotional and behavioural functioning is comprehensively evaluated.
  • a core part of neuropsychological assessment is the administration of neuropsychological tests for the formal assessment of cognitive function.
  • Performance in these tests is compared with norms appropriate to the patient's age, educational attainment, and cultural background. Testing often uses a set of performance-based questions, also known as a neuropsychological test battery.
  • the abilities tested include language processing, visuospatial processing, attention/con- centration, verbal learning and memory, visual learning and memory, executive functions, speed of processing, and sensory-perceptual functions.
  • MCCB MATRICS Consensus Cognitive Battery
  • the Montreal Cognitive Assessment 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; orientation to time and space.
  • the total possible score is 30 points; a score of 26 or above is considered normal; a score of 18-25 is considered mild cognitive impairment, a score of 10-17 is considered moderate cognitive impairment and a score less than 10 is considered severe cognitive impairment.
  • MMSE Mini-Mental State Examination
  • the MMSE Used repeatedly, the MMSE is suitable to measure changes in cognitive status.
  • the Mini-CogTM is a short cognitive impairment screening questionnaire. It combines a 3-word recall with a clock drawing test.
  • the clock drawing test assesses many cognitive areas that can be affected, such as executive function, visuospatial abilities, motor programming, and attention. One point is given for each of the three words correctly recalled after performing the clock drawing test; a correctly drawn clock is worth two points.
  • a score of ⁇ 4 indicates cognitive impairment.
  • the Screen for Cognitive Impairment in Psychiatry is a well-evaluated screening instrument for the examination of cognitive performance in psychiatric patients.
  • the SCIP consists of five subscales: verbal learning test - immediate (VLT-I), working memory test (WMT), verbal fluency test (VFT), verbal learning test - delayed (VLT-D) and processing speed test (PST).
  • VLT-I verbal learning test - immediate
  • WMT working memory test
  • VFT verbal fluency test
  • VLT-D verbal learning test - delayed
  • PST processing speed test
  • Cognitive dysfunction can also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of the various subtests.
  • the subtests are: Trail Making Test, Part A (testing speed of processing); Brief Assessment of Cognition in Schizophrenia, symbol coding subtest (speed of processing); Hopkins Verbal Learning Test-Revised, immediate recall, three learning trials only (verbal learning); Wechsler Memory Scale, 3rd ed., spatial span subtest (working memory (nonverbal)); Letter-Number Span test (working memory (verbal)); Neuropsychological Assessment Battery, mazes subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category fluency test, animal naming (speed of processing); Mayer-Salovey-Ca- ruso Emotional Intelligence Test, managing emotions branch (social cognition); and Continuous Performance Test, Identical Pairs version (attention/vigi lance).
  • test battery is appropriate to measure cognitive change.
  • VRM Verbal Recognition Memory
  • RVP Rapid Visual information Processing
  • SWM Spatial Working Memory
  • DSST Digit Symbol Substitution Test
  • Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is associated with blood flow, and temporal correlations of spontaneous blood oxygen level dependent (BOLD) signal fluctuations between different brain areas can be measured.
  • BOLD spontaneous blood oxygen level dependent
  • Resting-state fMRI can therefore 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 system.
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised in various disease states.
  • disease states which include 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 populations affected by cognitive dysfunction because it allows for the examination of functional connectivity while removing the demand of a task that may be confounded by potential cognitive or motor impairments.
  • Cognitive processes are reflected by functional connectivity of certain brain regions within and/or between regions located in different networks.
  • certain core networks also referred to as “higher-order cognitive networks” appear to be crucial for most mental activities.
  • the frontoparietal control network also referred to as frontoparietal network (FPN), central executive network (CEN) or executive network (EN), is typically associated with executive functions. These functions include keeping and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decisions and goal-directed behaviour.
  • the DMN contains regions in the brain that are most active when the person’s attention is not directed to any specific task.
  • the activity of the DMN is related to introspection, episodic memory, memory consolidation, social and self-related cognition, integration of cognitive and emotional processing, and task-unrelated free thoughts of mind wandering.
  • a third network is the salience network, also referred to as cingulo-opercular network. This network is involved in identifying salient stimuli and events, that is, what other brain networks need to attend to. This network has a central role in governing mental processes and behaviour.
  • a fourth network is the dorsal attention network (DAN).
  • the DAN is associated with top- down, goal-directed attention processes.
  • Resting state networks involved in cognition are also affected by mental or nervous system conditions which are a consequence of certain medical health conditions as well as in unspecified neurocognitive disorders.
  • resting state networks involved in cognition are affected by sleep disturbance, for instance, insomnia.
  • sleep disturbance for instance, insomnia.
  • cognitive dysfunction and impairment of sleep are correlated.
  • Cognitive function is deteriorated in patients suffering from sleep disturbance, and patients suffering from cognitive dysfunction often also suffer from impaired sleep. Treatment of Cognitive Dysfunction
  • cognitive dysfunction occurring in a patient suffering from a mental disorder or a nervous system disorder, or a medical health condition leading to an associated mental or nervous system condition can be treated.
  • cognitive dysfunction occurring in a patient suffering from sleep disturbance, for instance, insomnia can be treated.
  • Cognitive dysfunction in unspecified neurocognitive disorders can likewise be treated.
  • a treatment of cognitive dysfunction according to the invention leads to an improvement of the condition with which the cognitive dysfunction is associated.
  • Treatment according to the invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT administered to a patient disrupts established functional connectivity patterns within and/or between resting state networks. This disruption leads to a reset of the pathological ill-connected connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • influencing those networks by a therapy as described herein will lead to an improvement of the cognitive dysfunction and, if the patient treated suffers from a mental disorder or a nervous system disorder, also of that disorder; if the patient treated suffers from a medical health condition leading to an associated mental or nervous system condition, also of the associated mental or nervous system condition; if the patient treated suffers from sleep disturbance, for instance, insomnia, also of the sleep disturbance, for instance, insomnia; if the patient suffers from an unspecified neurocognitive disorder, also of one or more other symptoms of that disorder.
  • the inventors assessed clinical data relating to the use of 5-MeO-DMT in patients treated because of mental disease and noted particular improvements in cognitive dysfunction which is typically also observed in patients with other disorders.
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that particular subscore items, like items related to cognitive dysfunction, are relevant for other conditions in which cognitive dysfunction is based on similarly altered functional connectivity within and/or between the default mode network, the executive control network, the salience network, and the dorsal attention network.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • an aspect which can be treated by administration of 5-MeO-DMT is cognitive dysfunction, in particular concentration difficulties.
  • 5-MeO-DMT can be administered to patients to reduce or eliminate cognitive dysfunction, in particular concentration difficulties, in said patients.
  • the MADRS item that is of particular relevance to impaired concentration and memory is "concentration difficulties". This item represents difficulties in collecting one's thoughts mounting to incapacitating lack of concentration and is scored on a scale ranging from 0 to 6. The score is 0 if the patient has no difficulties in concentrating. The score is 2 in case of occasional difficulties in collecting one's thoughts. A score of 4 is assigned in case of difficulties in concentrating and sustaining thought which reduces ability to read or hold a conversation. The score is 6 if the patient is unable to read or converse without great difficulty. In the study group receiving the individualized dosing regimen, the aggregated score for the MADRS item "concentration difficulties" across all 8 patients was 30 at base line.
  • the treatment of a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates cognitive dysfunction.
  • the treatment of a patient with 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cognitive dysfunction, which is a deficit in, or an impairment of, one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition reduces or eliminates the cognitive dysfunction.
  • the cognitive dysfunction is reduced or eliminated if it 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, especially sustained attention.
  • a treatment of cognitive dysfunction according to the invention leads to an improvement of the condition with which the cognitive dysfunction is associated.
  • cognitive dysfunction may be considered a condition deserving treatment independent of any other conditions, disorders or symptoms an individual may suffer from, several mental disorders and disorders of the nervous system are associated with cognitive dysfunction. Notably, the relationship between cognitive dysfunction and mental disorder is bidirectional. Not only can mental disorders have a negative impact on cognitive function, but cognitive dysfunction can also be a contributing factor to the onset, progression and prognosis of mental or nervous system disorders.
  • resting state networks involved in cognitive dysfunction are also involved in the conditions listed above.
  • 5-MeO-DMT has the ability to disrupt established functional connectivity patterns of resting state networks. This disruption leads to a reset of the pathological ill-connected brain connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • Anxiety is sometimes defined as an "apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic symptoms of tension".
  • Anxiety is characterized by an intense, excessive, and persistent worry and fear about a situation that is only subjectively seen as menacing and is often accompanied by muscular tension, restlessness, fatigue, inability to catch one's breath, tightness in the abdominal region, nausea, and problems in concentration.
  • anxiety disorders or other mental or nervous system disorders associated with anxiety the 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 phobia, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance/medication-induced anxiety disorder.
  • Anxiety is moreover associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disturbance.
  • HAM-A Hamilton Anxiety Rating Scale
  • the scale is clinician-administered. It has 14 items which can be divided into a group of psychic items (1-6 and 14) measuring in particular mental agitation and psychological distress and into a group of somatic items (items 7-13) measuring in particular physical complaints related to anxiety.
  • the HAM-A items are shown in the table below.
  • a total score is obtained by summing the 14 items. The total score range is 0-56. Higher scores indicate more anxiety.
  • a score ⁇ 7 is considered to represent no or minimal anxiety; a score of 8-14 mild anxiety; a score of 15-23 moderate anxiety; a score > 24 severe anxiety.
  • the Beck Anxiety Inventory is a 21-item self-report questionnaire developed to assess anxiety, with a focus on somatic symptoms. The items are rated on a four-point Likert scale ranging from zero (not at all) to three (severely: I could barely stand it). The total score ranges from 0 to 63.
  • Subthreshold anxiety as the term is used herein in particular means that the patient has a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 but of less than 18 and/or a Beck Anxiety Inventory (BAI) score of at least 11 but of less than 16.
  • HAM-A Hamilton Rating Scale for Anxiety
  • BAI Beck Anxiety Inventory
  • Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is associated with blood flow, and temporal correlations of spontaneous blood oxygen level dependent (BOLD) signal fluctuations between different brain areas can be measured.
  • BOLD spontaneous blood oxygen level dependent
  • resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSN), which are a set of spatially distinct brain regions that show coordinated activity in the absence of any explicit cognitive task (i.e. , at rest).
  • the observed patterns, characterizing a network of brain regions with coherent patterns of signal variation, are called resting-state networks (RSN).
  • Resting-state fMRI can therefore 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 system.
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised in various disease states.
  • Such disease states which include certain forms of anxiety, 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.
  • anxiety and anxiety disorder pathophysiology involves aberrant connectivity between amygdala-frontal and frontal-striatal regions.
  • Anxiety and anxiety disorders are associated with specific alterations to resting state networks.
  • Anxiety and anxiety disorders show abnormalities within and/or between default mode network, salience network and sensorimotor network. The resting state balance within and/or between each of these networks differs in the different anxiety disorders.
  • anxiety occurring in a patient suffering from an anxiety disorder, or another mental disorder or nervous system disorder associated with anxiety can be treated.
  • anxiety occurring in a patient suffering from sleep disturbance, for instance, insomnia can be treated.
  • a treatment of anxiety according to the invention leads to an improvement of the condition with which the anxiety is associated.
  • Treatment according to the invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT administered to a patient disrupts established functional connectivity patterns within and/or between resting state networks. This disruption leads to a reset of the pathological ill-connected connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • influencing those networks by a therapy as described herein will lead to an improvement of the anxiety and, if the patient treated suffers from another mental disorder or nervous system disorder associated with anxiety, also of that disorder; if the patient treated suffers from sleep disturbance, for instance, insomnia, also of the sleep disturbance, for instance, insomnia.
  • sleep disturbance for instance, insomnia
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that particular subscore items, like items related to anxiety, are relevant for other conditions in which anxiety is based on similarly altered functional connectivity within and/or between resting state networks.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • an aspect which can be treated by administration of 5-MeO-DMT is anxiety.
  • 5-MeO-DMT can be administered to patients to reduce or eliminate anxiety in said patients.
  • the BPRS item that is of particular relevance in this context is "anxiety”. This item relates to reported apprehension, tension, fear, panic or worry. Possible scores are:
  • the aggregated score for the BPRS item "anxiety" across all 8 patients was 37 at base line.
  • the aggregated score for the BPRS item "anxiety" across all 4 patients was 25 at base line.
  • 5-MeO-DMT can be used to treat anxiety in patients, such as patients suffering from an anxiety disorder and patients suffering from a amental or nervous system disorder with associated anxiety.
  • the treatment of a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.
  • the MADRS item "inner tension” represents feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish. It is rated according to intensity, frequency, duration and the extent of reassurance called for.
  • the aggregated score for the MADRS item "inner tension" across all 8 patients was 26 at base line. After 2 hours, it was reduced to 11 which corresponds to an improvement of 15 points or 58%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 20 points or 77%. At day 7 after treatment, it was reduced to 12 which corresponds to an improvement of 14 points or 54%.
  • the aggregated score for the MADRS item "inner tension" across all 4 patients was 13 at base line. After 2 hours, it was reduced to 2 which corresponds to an improvement of 11 points or 85%. At day 1 after treatment, it was reduced to 3 which corresponds to an improvement of 10 points or 77%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 8 points or 62%.
  • a treatment according to the invention leads to a clinical response in a patient suffering from anxiety symptoms which is reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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.
  • a clinical response in a patient suffering from anxiety symptoms occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the clinical response in a patient suffering from anxiety symptoms, as reflected by at least 50% decrease of the HAM-A score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • a remission of the 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 , for instance after about 24 hours; 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 treatment of a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.
  • Psychomotor retardation involves a slowing down of thought and a reduction of physical movements in an individual.
  • Psychomotor impairment can cause a visible slowing of physical and emotional reactions.
  • Psychomotor retardation can be associated with a mental disorder or a nervous system disorder or some other medical conditions.
  • Mental or nervous system disorders which lead to, or are associated with, psychomotor retardation include disorders characterized by depressive episodes, for example, Major Depressive Disorder (MDD); Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Postpartum Depression (PPD); Seasonal Affective Disorder and Persistent Depressive Disorder; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorder, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DLB); Vascular Dementia and Parkinson's Disease Dementia; Parkinson’s Disease; Chronic Fatigue Syndrome.
  • MDD Major Depressive Disorder
  • BD Bipolar Disorder
  • PPD Postpartum Depression
  • PPD Postpartum Depression
  • SPD Seasonal Affective Disorder and Persistent Depressive Disorder
  • Mental and Behavioural Disorders due to Psychoactive Substance Use for example Substance Use Disorder (SUD);
  • Psychomotor retardation can also occur in a patient suffering from sleep disturbance, for instance, insomnia.
  • Psychomotor retardation can be assessed by measuring various aspects. These may include for instance 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) and others which are known in the art.
  • TMT trail making test
  • DSST digit symbol substitution test
  • GSM Gibson Spiral Maze Test
  • TMT trail making test
  • subjects In the trail making test (TMT), for instance, subjects must connect 25 circles that contain either numbers (TMT A) or a combination of numbers and letters (TMT B) in ascending order. Task requirements are similar for TMT-B, except that the subject must alternate between numbers and letters (1 , A, 2, B, 3, C and so on).
  • TMT A processing speed
  • TMT B cognitive flexibility
  • GSM Gibson Spiral Maze
  • the digit symbol substitution test measures also psychomotor speed and consists of digit-symbol pairs followed by a list of digits. Under each digit, the subject should write down the corresponding symbol as fast as possible. The score consists in the number of symbols correctly reported in 90 s.
  • a further example for a motor test is the finger tapping test.
  • SRRS Salpetriere Retardation Rating Scale
  • MARS Motor Agitation and Retardation Scale
  • the Salpetriere Retardation Rating Scale (SRRS), developed by Widlbcher assesses cognitive and motor aspects by fifteen items. The first three measure movement, specifically the quality of stride and slowness of limb, trunk, head, and neck movement. The next three items focus on speech including verbal flow, tone of voice, and length of response. Two items are designed to objectively measure cognitive function. These questions are based on the interview conversation and measure the patient’s ability to approach and expand on topics. The further items are subjective and assess rumination, fatigue, level of interest, perception of time, memory, and concentration. The last item of the scale relates to an overall assessment of the patient’s psychomotor retardation. The items are scaled from 0 (symptom absence) to 4 (severe) based on the severity of the presenting symptom, for a total score range of 0 to 60.
  • SRRS Salpetriere Retardation Rating Scale
  • the Motor Agitation and Retardation Scale assesses motor aspects only. It was designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five major body categories including eyes, face, voice, limbs, and trunk with a total of 19 items on the scale. Items of the eyes category include direction of gaze, amount of blinking, staring, and eye movement. Items associated with the face category include facial expression and facial expressivity. The category of voice has items that include volume, slurring, tone and time for onset. Items under the limbs category include hand, foot, and leg movement, stride, motor slowness, and tension in hands. The trunk category items include posture, immobility, and axial movement.
  • the severity of each item ranges from a 1 to a 4, with 4 being the most severe.
  • the retardation items include abnormal gait, immobility of trunk / proximal limbs, postural collapse, motor slowness (i.e. the limb and trunk category); lack of facial expressivity, downcast gaze (i.e. the eyes and face category); and reduced voice volume, slurring of speech, delayed speech onset, monotone speech (i.e. the voice category).
  • the MARS scale offers a rapid clinical assessment of motor signs.
  • Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is associated with blood flow, and temporal correlations of spontaneous blood oxygen level dependent (BOLD) signal fluctuations between different brain areas can be measured.
  • BOLD spontaneous blood oxygen level dependent
  • resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSN), which are a set of spatially distinct brain regions that show coordinated activity in the absence of any explicit cognitive task (i.e., at rest).
  • the observed patterns, characterizing a network of brain regions with coherent patterns of signal variation, are called resting-state networks (RSN).
  • Resting-state fMRI can therefore 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 system
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised in various disease states.
  • disease states which include certain forms of psychomotor retardation, 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.
  • abnormal functional connectivity was reported from somatosensory motor networks (SMN) to visual (VN), dorsal attention (DAN), and default mode networks which correlated with both psychomotor retardation and agitation in depressive disorders.
  • SSN somatosensory motor networks
  • VN visual
  • DAN dorsal attention
  • default mode networks which correlated with both psychomotor retardation and agitation in depressive disorders.
  • resting state networks involved in psychomotor retardation are affected by mental disorders or nervous system disorders, characterized by depressive episodes, for example, Major Depressive Disorder (MDD); Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Postpartum Depression (PPD); Seasonal Affective Disorder and Persistent Depressive Disorder; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorder, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DLB); Vascular Dementia and Parkinson's Disease Dementia; Parkinson Disease; Chronic Fatigue Syndrome.
  • MDD Major Depressive Disorder
  • BD Bipolar Disorder
  • PPD Postpartum Depression
  • PPD Postpartum Depression
  • SPD Seasonal Affective Disorder and Persistent Depressive Disorder
  • Mental and Behavioural Disorders due to Psychoactive Substance Use for example Substance Use Disorder (SUD); Psychotic
  • Resting state networks involved in psychomotor retardation are also affected by sleep disturbance, for instance, insomnia. In fact, psychomotor retardation and impairment of sleep are correlated.
  • psychomotor retardation in patients suffering from a mental disorder or a nervous system disorder can be treated.
  • psychomotor retardation occurring in a patient suffering from sleep disturbance, for instance, insomnia can be treated.
  • a treatment of psychomotor retardation according to the invention leads to an improvement of the condition with which the psychomotor retardation is associated.
  • Treatment according to the invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT administered to a patient disrupts established functional connectivity patterns within and/or between resting state networks. This disruption leads to a reset of the pathological ill-connected connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • influencing those resting state networks by a therapy as described herein will lead to an improvement of psychomotor retardation and, if the patient treated suffers from a mental disorder or a nervous system disorder, also of that disorder; if the patient treated suffers from sleep disturbance, for instance, insomnia, also of the sleep disturbance, for instance, insomnia.
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery-Asberg Depression Rating Scale (MADRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that particular subscore items, like items related to psychomotor retardation, are relevant for other conditions in which psychomotor retardation is based on similarly altered functional connectivity within and/or between the somatomotor/sensorimotor network, the visual network, the dorsal attention network and the default mode networks.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • 5-MeO-DMT is a compound suitable for treating patients presenting with these symptoms. More in particular, an aspect which can be treated by administration of 5-MeO-DMT, is psychomotor retardation. 5-MeO-DMT can be administered to patients to reduce or eliminate psychomotor retardation in said patients.
  • the MADRS scale item that is of particular relevance to psychomotor retardation is "lassitude", which represents a difficulty getting started or slowness initiating and performing everyday activities.
  • a score of 0 means that there is hardly any difficulty in getting started and no sluggishness.
  • a score of 2 is assigned if the patient has difficulties in starting activities.
  • a score of 4 means difficulties in starting simple routine activities which are carried out with effort.
  • a score of 6 is assigned in the case of complete lassitude, the patient being unable to do anything without help.
  • the aggregated score for the MADRS item "lassitude" across all 8 patients was 27 at base line.
  • the aggregated score for the MADRS item "lassitude" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 10 which corresponds to an improvement of 6 points or 38%. At day 1 after treatment, it was reduced to 0 which corresponds to an improvement of 16 points or 100%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81 %.
  • 5-MeO-DMT can be used to treat psychomotor retardation in patients, in particular patients also suffering from a mental disorder or a nervous system disorder or a sleep disturbance, for instance insomnia.
  • the treatment of a patient suffering from psychomotor retardation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates psychomotor retardation.
  • Symptoms such as anhedonia; emotional withdrawal and affective flattening are clustered together here as social/emotional withdrawal or detachment. Reduced social engagement is a further aspect associated with social/emotional withdrawal or detachment.
  • Anhedonia is the inability to experience pleasure. The patient does not suffer from anhedonia if there is subjectively no reduced ability to experience pleasure in usual activities. Anhedonia is mild in the case of slight reduction in pleasure from usually pleasurable activities; moderate in the case of significant reduction in pleasure from usually pleasurable activities or some pleasure from isolated activities retained; or severe in the case of complete inability to experience pleasure.
  • Anhedonia comprises consummatory (or liking) and anticipatory (or wanting) components.
  • Consummatory pleasure refers to the “in the moment” pleasure experienced by the subject directly engaged in an enjoyable activity, whereas anticipatory pleasure refers to the experience of pleasure related to future activities.
  • Affective flattening characterises the subjective sense of reduced intensity or range of feelings or emotions.
  • the subject does not show affective flattening if there is no sense of reduced intensity or range of feeling or emotions. It is mild in the case of slight constriction of range of affect, or transient reduction in range or intensity of feelings; moderate in the case of significant constriction of range or intensity of feelings with preservation of some emotions, e.g., inability to cry; and severe in the case of marked and pervasive constriction of range of affect or inability to experience usual emotions.
  • Emotional withdrawal or detachment is an inability or unwillingness to connect with other people on an emotional level.
  • the BPRS contains an item relating to emotional withdrawal, which is characterised as the deficiency in the subject's ability to relate emotionally during the interview situation.
  • this BPRS item there is no emotional withdrawal if there is no lack of emotional involvement shown by occasional failure to make reciprocal comments, occasionally appearing preoccupied, or smiling in a stilted manner, but spontaneously engages the interviewer most of the time.
  • There is a mild form of emotional withdrawal if there is a lack of emotional involvement shown by noticeable failure to make reciprocal comments, appearing preoccupied, or lacking in warmth, but responds to the interviewer when approached.
  • Reduced social engagement characterises subjective reports of reduced social and interpersonal engagement or interactions. There is no reduced social engagement if there are no reports of reduced social and interpersonal engagement or interactions. It is mild in the case of slight reduction in social engagement with no impairment in social or interpersonal function; moderate in the case of clear reduction in social engagement with some functional sequelae, e.g., avoiding some social engagements or conversations; and severe in the case of marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusing to answer the phone or see friends or family.
  • Social/emotional withdrawal or detachment can be associated with a mental disorder or a nervous system disorder or some other medical conditions.
  • Mental or nervous system disorders which lead to, or are associated with, social/emotional withdrawal or detachment include disorders characterized by depressive episodes, for example Major Depressive Disorder (MDD), Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder, Postpartum Depression (PPD), Seasonal Affective Disorder and Persistent Depressive Disorder; Anxiety Disorders, for example Generalised Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD); Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain and Fibromyalgia; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DLB); Vascular
  • the social/emotional withdrawal or detachment can also occur in a patient suffering from sleep disturbance, for instance, insomnia.
  • the social/emotional withdrawal or detachment can also occur in a patient suffering from medical health conditions leading to an associated mental or nervous system condition include Traumatic Brain Injury (TBI).
  • TBI Traumatic Brain Injury
  • Social/emotional withdrawal or detachment (herein often referred to as social/emotional withdrawal) or individual aspects thereof, such as anhedonia, emotional withdrawal and affective flattening, can be evaluated by different instruments, such as questionnaires or scales.
  • Questionnaires assess the mental status of a patient based on observations made by the patient himself/herself, caregivers or the clinician administering the questionnaire.
  • Questionnaires used to assess whether a patient suffers from a particular mental or nervous system disorder may comprise items related to social/emotional withdrawal or detachment.
  • the Snaith-Hamilton Pleasure Scale is a 14-item scale that measures anhedonia, i.e. , the inability to experience pleasure.
  • the items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes.
  • a score of 2 or less constitutes a “normal” score, while an “abnormal” score is defined as 3 or more.
  • Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Either of the “disagree” responses score one point, and either of the “agree” responses score 0 points. Thus, the final score ranges from 0 to 14.
  • the SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used for measuring anhedonia in depression, but it is also frequently used to assess anhedonia in other patient groups.
  • the SHAPS measures hedonic tone during the last few days with 14 hypothetically formulated items. However, due to the hypothetical nature of the items an appropriate shorter recall period can also be applied for an earlier assessment time point.
  • DARS Dimensional Anhedonia Rating Scale
  • hobbies, food/drink, social activities and sensory experience can be used for the assessment of anhedonia. It comprises 17 items assessing state anhedonia right now. The DARS is rated on a five-point Likert scale from 0 (not at all) to 4 (very much), higher values indicating less anhedonia. All items are summed up to a total score in the range of 0 to 68.
  • the Personality Inventory for DSM-5 (PID-5) - Adult is a 220 item self-rated personality trait assessment scale for adults age 18 and older. It assesses 25 personality trait facets including Anhedonia, Anxiousness, Attention Seeking, Callousness, Deceitfulness, De- pressivity, Distractibility, Eccentricity, Emotional Lability, Grandiosity, Hostility, Impul- sivity, Intimacy Avoidance, Irresponsibility, Manipulativeness, Perceptual Dysregulation, Perseveration, Restricted Affectivity, 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 trait facet Anhedonia contains the items 1 , 23, 26, 30R, 124, 155R, 157, 189 (reverse scored items are marked with the letter “R”)
  • the trait facet Withdrawal contains the items 10, 20, 75, 82, 136, 146, 147, 161 , 182, 186
  • the trait facet Intimacy Avoidance contains the items 89, 97R, 108, 120, 145, 203.
  • the measure is completed by the individual prior to a visit with the clinician. Each item asks the individual to rate how well the item describes him or her generally.
  • Each item on the measure is rated on a 4-point scale.
  • the items are reverse-coded prior to entering into scale score computations.
  • the scores on the items within each trait facet should be summed and entered in the appropriate raw facet score box.
  • the clinician is asked to calculate and use average scores for each facet and domain.
  • the average scores reduce the overall score as well as the scores for each domain to a 4-point scale, which allows the clinician to think of the individual’s personality dysfunction relative to observed norms.
  • An average domain score is calculated by summing and then averaging the 3 facet scores contributing primarily to the specific domain.
  • High scores on a facet or domain may indicate significant and problematic areas for the individual receiving care that might warrant further assessment, treatment, and followup.
  • Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is associated with blood flow, and temporal correlations of spontaneous blood oxygen level dependent (BOLD) signal fluctuations between different brain areas can be measured.
  • BOLD spontaneous blood oxygen level dependent
  • resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSN), which are a set of spatially distinct brain regions that show coordinated activity in the absence of any explicit cognitive task (i.e. , at rest).
  • the observed patterns, characterizing a network of brain regions with coherent patterns of signal variation, are called resting-state networks (RSN).
  • Resting-state fMRI can therefore 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 system.
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised in various disease states.
  • disease states which include certain forms of social/emotional withdrawal or detachment, 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.
  • RSNs are also involved in anhedonia, which is one key aspect of social/emotional withdrawal or detachment. More specifically, anhedonia is associated with visual network hyperconnectivity and expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia also involves decreased between-network connectivity among the DMN, salience, DAN, somatomotor, and visual networks.
  • DAN dorsal attention network
  • DN default mode network
  • the dorsal DMN is of particular interest in the development of psychopathy due to the functions associated with it. Specifically, the dorsal DMN, and the regions it connects (the medial prefrontal cortex and posterior cingulate cortex (PCC)), underpin affective, social and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are linked to the affective and interpersonal differences that define the disorder.
  • PCC posterior cingulate cortex
  • patients suffering from social/emotional withdrawal or detachment show altered functional connectivity within and/or between RSNs when compared to healthy, age- matched controls. Alterations are observed within and/or between the DMN, the salience, DAN, somatomotor, and visual networks.
  • RSNs involved in social/emotional withdrawal or detachment are affected by mental or nervous system disorders, such as disorders characterized by depressive episodes, for example Major Depressive Disorder (MDD), Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder, Postpartum Depression (PPD), Seasonal Affective Disorder and Persistent Depressive Disorder; Anxiety Disorders, for example Generalised Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD); Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain and Fibromyalgia; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DL
  • TBI Traumatic Brain Injury
  • Resting state networks involved in social/emotional withdrawal or detachment are also affected by sleep disturbance, for instance, insomnia.
  • sleep disturbance for instance, insomnia.
  • social/emotional withdrawal or detachment and impairment of sleep are correlated.
  • social/emotional withdrawal or detachment occurring in a patient suffering from a mental disorder or a nervous system disorder can be treated.
  • social/emotional withdrawal or detachment occurring in a patient suffering from sleep disturbance, for instance, insomnia can be treated.
  • a treatment of social/emotional withdrawal or detachment according to the invention leads to an improvement of the condition with which the social/emotional withdrawal or detachment is associated.
  • Treatment according to the invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT administered to a patient disrupts established functional connectivity patterns within and/or between resting state networks. This disruption leads to a reset of the pathological ill-connected connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • influencing those networks by a therapy as described herein will lead to an improvement of the social/emotional withdrawal or detachment and, if the patient treated suffers from a mental disorder or a nervous system disorder, also of that disorder; if the patient treated suffers from sleep disturbance, for instance, insomnia, also of the sleep disturbance, for instance, insomnia.
  • sleep disturbance for instance, insomnia
  • the inventors assessed clinical data relating to the use of 5-MeO-DMT in patients treated because of mental disease and noted particular improvements in social/emotional withdrawal or detachment which is typically also observed in patients with other disorders.
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that particular subscore items, like items related to social/emotional withdrawal or detachment, are relevant for other conditions in which social/emotional withdrawal or detachment is based on similarly altered functional connectivity within and/or between the default mode network, the salience, dorsal attention, somatomotor, and visual networks.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • an aspect which can be treated by administration of 5-MeO-DMT is social/emotional withdrawal or detachment, in particular anhedonia, emotional withdrawal and/or affective flattening.
  • a further treated aspect is reduced social engagement.
  • 5-MeO-DMT can be administered to patients to reduce or eliminate social/emo- tional withdrawal or detachment, in particular anhedonia, emotional withdrawal and/or affective flattening, in said patients.
  • reduced social engagement is improved, i.e. it is reduced or eliminated.
  • the MADRS scale item "inability to feel”, that is of particular relevance to social/emo- tional withdrawal or detachment, represents the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced.
  • a score of 0 indicates normal interest in the surroundings and in other people, a score of 2 indicates a reduced ability to enjoy usual interests.
  • a score of 4 is assigned in case of a loss of interest in the surroundings and a loss of feelings for friends and acquaintances.
  • a score of 6 reflects the experience of being emotionally paralysed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends.
  • the aggregated score for the MADRS item "inability to feel" across all 8 patients was 36 at base line. After 2 hours, it was reduced to 12 which corresponds to an improvement of 24 points or 67%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 34 points or 94%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 30 points or 83%.
  • the aggregated score for the MADRS item "inability to feel" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 9 which corresponds to an improvement of 7 points or 44%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%. At day 7 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%.
  • BPRS scale items which are of particular relevance to social/emotional withdrawal or detachment are " emotional withdrawal” and “blunted affect”.
  • the BPRS item “emotional withdrawal” relates to a deficiency in the patient's ability to relate emotionally during the interview situation. Possible scores are:
  • Emotional contact not present much of the interview because subject does not elaborate responses, fails to make eye contact, doesn't seem to care if interviewer is listening, or may be preoccupied with psychotic material.
  • the aggregated score for the BPRS item "emotional withdrawal" was 13 at base line. After 3 hours, it was reduced to 8 which corresponds to an improvement of 5 points or 38%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 5 points or 38%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 5 points or 38%.
  • the aggregated score for the BPRS item "emotional withdrawal" was 13 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 2 points or 15%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 5 points or 38%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 7 points or 54%.
  • the BPRS item “blunted affect” relates to a restricted range in emotional expressiveness of face, voice, and gestures as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are:
  • Emotional range is noticeably diminished, patient doesn't show emotion, smile, or react to distressing topics except infrequently.
  • Voice tone is monotonous or there is noticeable decrease in spontaneous movements. Displays of emotion or gestures are usually followed by a return to flattened affect.
  • the aggregated score for the BPRS item "blunted affect" was 15 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 4 points or 27%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%.
  • the aggregated score for the BPRS item "blunted affect" was 11 at base line. After 3 hours, it was reduced to 8 which corresponds to an improvement of 3 points or 27%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 5 points or 45%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 6 points or 55%.
  • the scores of the scale items that are of particular relevance to social/emotional withdrawal or detachment i.e., "inability to feel” (MADRS), “emotional withdrawal” (BPRS) and “blunted affect” (BPRS) are markedly improved.
  • MADRS inability to feel
  • BPRS emotional withdrawal
  • BPRS bluented affect
  • 5-MeO-DMT can be used to treat social/emotional withdrawal or detachment in patients, in particular in patients also suffering from a mental disorder or a nervous system disorder or a sleep disturbance, for instance insomnia.
  • the treatment of a patient suffering from so- cial/emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates social/emotional withdrawal or detachment.
  • helplessness and hopelessness characterize the subjective sense of pessimism or gloom regarding the future, inability to cope, or sense of loss of control.
  • helplessness and hopelessness are mild in the case of occasional and mild feelings of not being able to cope as usual or pessimism; moderate in the case the patient often feels unable to cope or has significant feelings of helplessness or hopelessness which lift at times; or severe if there are marked and persistent feelings of pessimism, helplessness, or hopelessness.
  • Feelings of worthlessness characterize the subjective sense or thoughts of decreased self-value or self-worth. There is no worthlessness if the patient does not have such feelings. They may be mild, i.e., slight decrease in sense of self-worth; moderate; i.e., some thoughts of worthlessness and decreased self-worth; or severe, i.e., marked, pervasive, or persistent feelings of worthlessness, e.g., feels others better off without them, unable to appreciate positive attributes.
  • Negative thinking can be associated with a mental disorder or a nervous system disorder or some other medical conditions.
  • Mental or nervous system disorders which lead to, or are associated with, negative thinking include disorders characterized by depressive episodes, for example, Major Depressive Disorder (MDD), Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder, Postpartum Depression (PPD), Seasonal Affective Disorder and Persistent Depressive Disorder; Anxiety Disorder, for example Generalised Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD); Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example, Chronic Pain; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorder, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Eating Disorders; Attention Defic
  • the negative thinking can also occur in a patient suffering from sleep disturbance, for instance, insomnia.
  • TBI Traumatic Brain Injury
  • Negative thinking or individual aspects thereof, such as worthlessness, helplessness and hopelessness, and guilt, can be evaluated by different instruments, such as questionnaires or scales.
  • Questionnaires assess the mental status of a patient based on observations made by the patient himself/herself, caregivers or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a particular mental or nervous system disorder may comprise items related to negative thinking.
  • Instruments evaluating relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule - Expanded Form (PANAS-X) or the State Hope Scale (SHS).
  • the State Shame and Guilt Scale (SSGS) is a self-rating scale of in-the-moment (state) feelings of shame, and guilt experiences. It comprises two subscales, a shame and a guilt subscale.
  • the shame subscale comprises items 1 , 3, 5, 7, 9.
  • the guilt subscale comprises items 2, 4, 6, 8, 10. All items are scored in a positive direction and are rated on a 5-point Likert scale. It contains some statements which may or may not describe how the patient is feeling right now. A higher score indicates a more intense feeling of shame or guilt.
  • PANAS-X The Positive and Negative Affect Schedule - Expanded Form
  • the PANAS-X measures 11 specific affects: Fear, Sadness, Guilt, Hostility, Shyness, Fatigue, Surprise, Joviality, Self-Assurance, Attentiveness, and Serenity.
  • the PANAS-X thus provides for mood measurement at two different levels.
  • the basic negative emotion scales are fear, hostility, guilt and sadness, while the scale guilt encompasses six items: guilty, ashamed, blameworthy, angry at self, disgusted with self, dissatisfied with self.
  • investigators facing more severe time constraints can select and assess only those scales that are most relevant to their research.
  • the PANAS-X is simple and easy to administer. Most subjects complete the entire 60- item schedule in 10 minutes or less. This scale consists of a number of words and phrases that describe different feelings and emotions. While it should be indicated to what extent the patient has felt this way during the past few weeks, it has been found that the trait scores on the PANAS-X scales are stable over time, including “at the present moment”, “today” and during “the past few days”, indicating that an appropriate shorter recall period can be applied.
  • the State Hope Scale has three agency and three pathways items to which respondents describe themselves in terms of how they are "right now.”
  • the agency subscale score is derived by summing items 2, 4 and 6, relating to the perceived capacity to use one's pathways to reach desired goals; the pathways subscale score is derived by adding the items 1 , 3 and 5, relating to thinking that is used to identify possible ways to achieve a goal.
  • the total State Hope Scale score is derived by summing the three agency and the three pathways items. Scores can range from a low of 6 to a high of 48, wherein higher hope is reflected by a higher score on this scale. Negative thinking or aspects thereof are also reflected in other scales such as HAM-D, the MADRS, the BPRS or the BDRS, wherein relevant items thereof may be commonly applicable for assessing negative thinking or aspects thereof.
  • Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is associated with blood flow, and temporal correlations of spontaneous blood oxygen level dependent (BOLD) signal fluctuations between different brain areas can be measured.
  • BOLD spontaneous blood oxygen level dependent
  • resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSN), which are a set of spatially distinct brain regions that show coordinated activity in the absence of any explicit cognitive task (i.e. , at rest).
  • the observed patterns, characterizing a network of brain regions with coherent patterns of signal variation, are called resting-state networks (RSN).
  • Resting-state fMRI can therefore 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 system.
  • RSNs have been shown to be responsible for various aspects of complex brain function, and it has been found that these connectivity networks are compromised in various disease states.
  • Such disease states which include certain forms of negative thinking, 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.
  • MDD Major Depressive Disorder
  • DNN Default Mode Network
  • Dysfunctional connectivity in resting state networks has been also reported for patients with repetitive negative thinking (RNT) including an altered connectivity of the left Executive Control Network and the Anterior Salience Network with the ventral Default Mode Network.
  • RNT repetitive negative thinking
  • patients suffering from negative thinking show altered functional connectivity within and/or between resting state networks when compared to healthy, age-matched controls. Alterations are observed within and/or between at least the default mode network, the executive control network, the salience network, the affective network, and the prefrontal cortex.
  • RSNs involved in negative thinking are affected by mental or nervous system disorders, such as disorders characterized by depressive episodes, for example, Major Depressive Disorder (MDD), Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder, Postpartum Depression (PPD), Seasonal Affective Disorder and Persistent Depressive Disorder; Anxiety Disorder, for example Generalised Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD); Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example, Chronic Pain; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorder, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Eating Disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality Disorders, for example Schizotypal Personality
  • Resting state networks involved in negative thinking are also affected by mental or nervous system conditions which are a consequence of certain medical health conditions, such as Traumatic Brain Injury (TBI). Resting state networks involved in negative thinking are also affected by sleep disturbance, for instance, insomnia. In fact, negative thinking and impairment of sleep are correlated.
  • TBI Traumatic Brain Injury
  • negative thinking occurring in a patient suffering from a mental disorder or a nervous system disorder can be treated.
  • negative thinking occurring in a patient suffering from sleep disturbance, for instance, insomnia can be treated.
  • a treatment of negative thinking according to the invention leads to an improvement of the condition with which the negative thinking is associated.
  • Treatment according to the invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT administered to a patient disrupts established functional connectivity patterns within and/or between resting state networks. This disruption leads to a reset of the pathological ill-connected connections as the networks reconnect. New, healthy functional connections are established with persistent effects.
  • influencing those networks by a therapy as described herein will lead to an improvement of the negative thinking and, if the patient treated suffers from a mental disorder or a nervous system disorder, also of that disorder; if the patient treated suffers from sleep disturbance, for instance, insomnia, also of the sleep disturbance, for instance, insomnia.
  • sleep disturbance for instance, insomnia
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that particular subscore items, like items related to negative thinking, are relevant for other conditions in which negative thinking is based on similarly altered functional connectivity within and/or between the default mode network, the executive control network, the salience network, the affective network, and the prefrontal cortex.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • an aspect which can be treated by administration of 5-MeO-DMT is negative thinking, in particular feelings of worthlessness, helplessness and hopelessness, and/or guilt.
  • 5-MeO-DMT can be administered to patients to reduce or eliminate negative thinking, in particular feelings of worthlessness, helplessness and hopelessness, and/or guilt, in said patients.
  • the MADRS scale item that is of particular relevance to negative thinking is "pessimistic thoughts", which represents thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and ruin.
  • a score of 0 is assigned if there are no pessimistic thoughts.
  • the score is 2 in the case of fluctuating ideas of failure, self-reproach or self-depreciation.
  • a score means persistent self-accusations, or definite but still rational ideas of guilt or sin as well as the patient being increasingly pessimistic about the future.
  • a score of 6 is assigned in the case of delusions of ruin, remorse or unredeemable sin and self-accusations which are unreasonable and unshakable.
  • the aggregated score for the MADRS item "pessimistic thoughts" across all 8 patients was 28 at base line.
  • the aggregated score for the MADRS item "pessimistic thoughts" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 8 which corresponds to an improvement of 8 points or 50%. At day 1 after treatment, it was reduced to 7 which corresponds to an improvement of 9 points or 56%.
  • the BPRS item that is of particular relevance to negative thinking is "guilt feelings”. This item relates to over concern or remorse for past behaviour. Possible scores are:
  • the aggregated score for the BPRS item "guilt feelings" across all 8 patients was 34 at base line.
  • the aggregated score for the BPRS item "guilt feelings" across all 4 patients was 18 at base line.
  • the score of the MADRS scale item that is of particular relevance to negative thinking, "pessimistic thoughts”, is markedly improved, as is the score of the BPRS item "guilt feelings”.
  • the inventors conclude that 5-MeO-DMT can be used to treat negative thinking in patients, in particular patients also suffering from a mental disorder or a nervous system disorder or a sleep disturbance, for instance insomnia.
  • the treatment of a patient suffering from negative thinking with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates negative thinking.
  • Maternal functioning includes aspects of maternal competence relating to interactions with the infant(s) as well as maternal self-care.
  • Maternal functioning including the emotional aspect of mothering, is also important for the child’s development.
  • the quality of mother-child interaction in the year after birth affects infant development.
  • High levels of maternal functioning are likely to correlate with positive infant development outcomes.
  • impaired functioning in the postpartum period might impede optimal infant development.
  • the Barkin Index of Maternal Functioning was designed to measure functioning in the year after childbirth.
  • the BIMF is a 20-item self-report measure of functioning. Each item is assigned a score between 0 and 6 so that the maximum total score is 120. The higher the score, the better maternal functioning is rated.
  • the BIMF identifies the key functional domains of a mother during the postnatal period as: self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
  • a BIMF score of 95 or below is considered herein as representing slightly compromised maternal functioning
  • score of 80 or below is considered herein as representing compromised maternal functioning
  • a score of 65 or below is considered herein as representing severely compromised maternal functioning.
  • the invention in particular allows improving maternal functioning in patients having a score of 80 or below before treatment and in patients having a score of even 65 or below.
  • the present invention allows treating patients suffering from a mental or nervous system disorder.
  • the treatment does not only lead to reductions in scores assessing the severity of depression, but also improves maternal functioning as discussed in detail below.
  • 5-MeO-DMT assessed clinical data relating to the use of 5-MeO-DMT in patients treated because of mental disease and noted particular improvements in disease aspects typically also observed in patients with a mental or nervous system disorder.
  • the inventors in particular noted improvements in various symptoms and combinations of symptoms which the inventors determined to be also associated with maternal functioning.
  • the data stem from a recently completed clinical trial investigating the use of 5-MeO- DMT in the treatment of patients diagnosed with Treatment Resistant Depression (TRD; see also the examples section below). The results are confirmed by a recent trial in patients suffering from Post Partum Depression (see the example section below).
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that several of the subscore items are of particular relevance for a mental or nervous system disorder patients and are related to maternal functioning.
  • MADRS Montgomery Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • a treatment according to the invention reduces or eliminates (or improves or eliminates) an aspect of the disease.
  • the aspect is assessed on the MADRS scale, there is an improvement by at least one point (reduction) or the patient is in complete remission after the treatment (elimination), i.e. , the respective aspect is scored 0. If the aspect is assessed on the BPRS scale, there is an improvement by at least one point (reduction) or the patient is in complete remission after the treatment (elimination), i.e., the respective aspect is scored 1.
  • a clinical response may also be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score.
  • CGI-S Clinical Global Impression - Severity
  • a reduction in the CGI-S score means that the CGI-S is reduced by at least 1.
  • the CGI-S is reduced by at least 2 and/or to a score of 0. It is especially preferred if the CGI-S is reduced by at least 3 and/or to a score of 0.
  • the inventors further consider that improvements observed in certain MADRS items will translate into improvements in aspects of maternal functioning.
  • the MADRS item "inner tension” represents feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish. It is rated according to intensity, frequency, duration and the extent of reassurance called for.
  • a score of 0 is assigned if the patient is placid and there is only fleeting inner tension.
  • a score of 2 is assigned if there are occasional feelings of edginess and ill-defined discomfort.
  • the score is 4 if there are continuous feelings of inner tension or intermittent panic which the patient can only master with some difficulty.
  • the score is 6 in case of unrelenting dread or anguish and overwhelming panic.
  • the inventors have determined that increases in the score of the MADRS item "inner tension” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "inner tension” impair mother-child interaction as well as psychological well-being of the mother as assessed by the BIMF.
  • the aggregated score for the MADRS item "inner tension" across all 8 patients was 26 at base line. After 2 hours, it was reduced to 11 which corresponds to an improvement of 15 points or 58%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 20 points or 77%. At day 7 after treatment, it was reduced to 12 which corresponds to an improvement of 14 points or 54%.
  • the aggregated score for the MADRS item "inner tension" across all 4 patients was 13 at base line. After 2 hours, it was reduced to 2 which corresponds to an improvement of 11 points or 85%. At day 1 after treatment, it was reduced to 3 which corresponds to an improvement of 10 points or 77%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 8 points or 62%.
  • 5-MeO-DMT can be used to treat a mental or nervous system disorder patients to achieve a reduction or elimination of inner tension.
  • An improvement in inner tension is reflected by at least an improvement in the score of the MADRS item inner tension about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in inner tension as reflected by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in inner tension as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of inner tension achieved by treating a a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • inner tension also affects other aspects of a mental or nervous system disorder
  • the inventors conclude that the observed improvement in the “inner tension” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “lassitude” represents a difficulty getting started or slowness initiating and performing everyday activities.
  • a score of 0 means that there is hardly any difficulty in getting started and no sluggishness.
  • a score of 2 is assigned if the patient has difficulties in starting activities.
  • a score of 4 means difficulties in starting simple routine activities which are carried out with effort.
  • a score of 6 is assigned in case of complete lassitude, the patient being unable to do anything without help.
  • the inventors have determined that increases in the score of the MADRS item “lassitude” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “lassitude” impair infant care, self-care, psychological well-being, management and adjustment.
  • the aggregated score for the MADRS item “lassitude” across all 8 patients was 27 at base line. After 2 hours, it was reduced to 10 which corresponds to an improvement of 17 points or 63%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 22 points or 81 %. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 24 points or 89%.
  • the aggregated score for the MADRS item “lassitude” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 10 which corresponds to an improvement of 6 points or 38%. At day 1 after treatment, it was reduced to 0 which corresponds to an improvement of 16 points or 100%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81 %.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of lassitude.
  • An improvement in lassitude is reflected by at least an improvement in the score of the MADRS item lassitude about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in lassitude as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of lassitude achieved by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased Bl MF score will also be observed on day 1 , for instance, after about 24 hours; 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 inventors conclude that the observed improvement in the “lassitude” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “inability to feel” represents the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced.
  • a score of 0 indicates normal interest in the surroundings and in other people, a score of 2 reduced ability to enjoy usual interests.
  • a score of 4 is assigned in case of a loss of interest in the surroundings and a loss of feelings for friends and acquaintances.
  • a score of 6 reflects the experience of being emotionally paralysed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends.
  • the inventors have determined that increases in the score of the MADRS item “inability to feel” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “inability to feel” impair mother-child interaction and psychological well-being.
  • the aggregated score for the MADRS item “inability to feel” across all 8 patients was 36 at base line. After 2 hours, it was reduced to 12 which corresponds to an improvement of 24 points or 67%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 34 points or 94%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 30 points or 83%.
  • the aggregated score for the MADRS item “inability to feel” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 9 which corresponds to an improvement of 7 points or 44%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%. At day 7 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of inability to feel.
  • An improvement in inability to feel is reflected by at least an improvement in the score of the MADRS item inability to feel about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in inability to feel as reflected by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in inability to feel as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of inability to feel by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed 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.13
  • inability to feel also affects other aspects of a mental or nervous system disorder, the inventors conclude that the observed improvement in the "inability to feel" item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item "concentration difficulties” represents difficulties in collecting one's thoughts mounting to incapacitating lack of concentration.
  • the score is 0 if the patient has no difficulties in concentrating.
  • the score is 2 in case of occasional difficulties in collecting one's thoughts.
  • a score of 4 is assigned in case of difficulties in concentrating and sustaining thought which reduces ability to read or hold a conversation.
  • the score is 6 if the patient is unable to read or converse without great difficulty.
  • the inventors have determined that increases in the score of the MADRS item "concentration difficulties" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "concentration difficulties” impair infant care as well as management.
  • the aggregated score for the MADRS item "concentration difficulties" across all 8 patients was 30 at base line. After 2 hours, it was reduced to 11 which corresponds to an improvement of 19 points or 63%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 29 points or 97%. At day 7 after treatment, it was reduced to 9 which corresponds to an improvement of 21 points or 70%.
  • the aggregated score for the MADRS item "concentration difficulties" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 14 points or 88%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of concentration difficulties.
  • An improvement in concentration difficulties is reflected by at least an improvement in the score of the MADRS item concentration difficulties about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • An improvement in concentration difficulties as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in concentration difficulties as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of concentration difficulties by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed 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.
  • concentration difficulties also affect other aspects of a mental or nervous system disorder, the inventors conclude that the observed improvement in the “concentration difficulties” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “pessimistic thoughts” represents thoughts of guilt, inferiority, self- reproach, sinfulness, remorse and ruin.
  • a score of 0 is assigned if there are no pessimistic thoughts.
  • the score is 2 in case of fluctuating ideas of failure, self-reproach or self-depreciation.
  • a score means persistent self-accusations, or definite but still rational ideas of guilt or sin as well as the patient being increasingly pessimistic about the future.
  • a score of 6 is assigned in case of delusions of ruin, remorse or unredeemable sin and self-accusations which are educa and unshakable.
  • the inventors have determined that increases in the score of the MADRS item "pessimistic thoughts" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “pessimistic thoughts” impair psychological wellbeing, social support and management.
  • the aggregated score for the MADRS item “pessimistic thoughts” across all 8 patients was 28 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 21 points or 75%. At day 1 after treatment, it was reduced to 4 which corresponds to an improvement of 24 points or 86%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 25 points or 89%.
  • the aggregated score for the MADRS item “pessimistic thoughts” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 8 which corresponds to an improvement of 8 points or 50%. At day 1 after treatment, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 8 points or 50%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of pessimistic thoughts.
  • An improvement in pessimistic thoughts is reflected by at least an improvement in the score of the MADRS item pessimistic thoughts about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in pessimistic thoughts as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in pessimistic thoughts as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of pessimistic thoughts by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased Bl MF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • pessimistic thoughts also affects other aspects of a mental or nervous system disorder, the inventors conclude that the observed improvement in the “pessimistic thoughts” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “reduced sleep” represents the experience of reduced duration or depth of sleep compared to the subject’s own normal pattern when well.
  • a score of 0 is assigned when the subject sleeps as usual.
  • a score of 2 reflects slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
  • a score of 4 means that sleep is reduced or broken by at least two hours.
  • a score of 6 means less than two or three hours sleep.
  • the inventors have determined that increases in the score of the MADRS item “reduced sleep” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “reduced sleep” impair self-care, psychological well-being and management. Conversely, improvements regarding this MADRS item lead to improvements in maternal functioning, in particular in the Bl MF functional domains self-care, psychological wellbeing and/or management.
  • the aggregated score for the MADRS item “reduced sleep” across all 8 patients was 25 at base line.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 9 which corresponds to an improvement of 16 points or 64%.
  • the aggregated score for the MADRS item “reduced sleep” across all 4 patients was 12 at base line. At day 1 after treatment, it was reduced to 10 which corresponds to an improvement of 2 points or 17%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 6 points or 50%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of reduced sleep.
  • the reduction or elimination of reduced sleep is reflected by at least an improvement in the score of the MADRS item reduced sleep on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • An improvement in reduced sleep as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in reduced sleep as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of reduced sleep by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 24 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • a further aspect of a mental or nervous system disorder which can be treated by administration of 5-MeO-DMT, is suicidal ideation.
  • 5-MeO-DMT can be administered to mental or nervous system disorder patients to reduce or eliminate suicidal ideation in said patients.
  • “Suicidal thoughts” represents a feeling that life is not worth living, that a natural death would be welcome, having suicidal thoughts, and/or making the preparations for suicide. Suicidal attempts should not in themselves influence the rating for this MADRS item.
  • a score of 0 means that the patient enjoys life.
  • a score of 2 is assigned if the mental or nervous system disorder patient is weary of life, and/or has only fleeting suicidal thoughts.
  • a score of 4 means the patient feels they would be better off dead, suicidal thoughts are common and suicide is considered as a possible solution but the patient has no specific plans or intention.
  • a score of 6 is assigned in case the patient has explicit plans for suicide and/or is making active preparations.
  • This MADRS scale item is of particular relevance to suicidal ideation.
  • the inventors have determined that increases in the score of the MADRS item “suicidal thoughts” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “suicidal thoughts” impair self-care, psychological well-being and management. Conversely, improvements regarding this MADRS item lead to improvements in maternal functioning, in particular in the Bl MF functional domains self-care, psychological wellbeing and/or management.
  • the aggregated score for the MADRS item “suicidal thoughts” across all 8 patients was 11 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 8 points or 73%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 10 points or 91 %. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 8 points or 73%.
  • the aggregated score for the MADRS item “suicidal thoughts” across all 4 patients was 8 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 5 points or 63%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 3 points or 38%. At day 7 after treatment, it was reduced to 7 which corresponds to an improvement of 1 point or 13%.
  • the treatment of a mental or nervous system disorder patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.
  • the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score of the MADRS item suicidal thoughts about 2 hours; on day 1 , for instance, after about 24 hours, 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI-S Clinical Global Impression - Severity
  • a reduction in the Clinical Global Impression - Severity (CGI-S) score occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in suicidal ideation as assessed by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in suicidal ideation as assessed by a reduction of the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of suicidal thoughts by treating a mental or nervous system disorder patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • suicidal thoughts also affects other aspects of a mental or nervous system disorder, the inventors conclude that the observed improvement in the “suicidal thoughts” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the BPRS item “emotional withdrawal” relates to a deficiency in the patient’s ability to relate emotionally during the interview situation. Possible scores are:
  • Emotional contact not present much of the interview because subject does not elaborate responses, fails to make eye contact, doesn’t seem to care if interviewer is listening, or may be preoccupied with psychotic material.
  • the inventors have determined that increases in the score of the BPRS item “emotional withdrawal” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “emotional withdrawal” impair psychological well-being, mother-child interaction and social support.
  • the aggregated score for the BPRS item “emotional withdrawal” was 13 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 2 points or 15%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 5 points or 38%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 7 points or 54%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of emotional withdrawal.
  • the reduction or elimination of emotional withdrawal is reflected by at least an improvement in the score of the BPRS item emotional withdrawal about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in emotional withdrawal as reflected by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in emotional withdrawal as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of emotional withdrawal by treating a mental or nervous system disorder patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased Bl MF score will also be observed on day 1 , for instance, after about 24 hours; 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 inventors conclude that the observed improvement in the "emotional withdrawal" item on the BPRS will additionally contribute to an overall improvement in maternal functioning.
  • the BPRS item "blunted affect” relates to a restricted range in emotional expressiveness of face, voice, and gestures as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are:
  • Emotional range is noticeably diminished, patient doesn't show emotion, smile, or react to distressing topics except infrequently.
  • Voice tone is monotonous or there is noticeable decrease in spontaneous movements. Displays of emotion or gestures are usually followed by a return to flattened affect.
  • the inventors have determined that increases in the score of the BPRS item "blunted affect” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "blunted affect” impair psychological well-being and motherchild interaction. Conversely, improvements regarding this BPRS item lead to improvements in maternal functioning, in particular in the BIMF functional domains psychological well-being and/or mother-child interaction.
  • the aggregated score for the BPRS item "blunted affect" was 15 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 4 points or 27%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%.
  • the aggregated score for the BPRS item "blunted affect" was 11 at base line. After 3 hours, it was reduced to 8 which corresponds to an improvement of 3 points or 27%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 5 points or 45%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 6 points or 55%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of blunted affect.
  • the reduction or elimination of blunted affect is reflected by at least an improvement in the score of the BPRS item blunted affect about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in blunted affect as reflected by at least a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in blunted affect as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of blunted affect by treating a mental or nervous system disorder patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • blunted affect also affects other aspects of a mental or nervous system disorder
  • the inventors conclude that the observed improvement in the “blunted affect” item on the BPRS will additionally contribute to an overall improvement in maternal functioning.
  • the BPRS item “guilt feelings” relates to over concern or remorse for past behavior. Possible scores are:
  • the aggregated score for the BPRS item “guilt feelings” across all 8 patients was 34 at base line. After 3 hours, it was reduced to 14 which corresponds to an improvement of 20 points or 59%. At day 1 after treatment, it was reduced to 11 which corresponds to an improvement of 23 points or 68%. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 24 points or 71%.
  • the aggregated score for the BPRS item “guilt feelings” across all 4 patients was 18 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 9 points or 50%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of guilt feelings.
  • the reduction or elimination of guilt feelings is reflected by at least an improvement in the score of the BPRS item guilt feelings about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in guilt feelings as reflected by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement in guilt feelings as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of guilt feelings by treating a mental or nervous system disorder patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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 BPRS item "anxiety” relates to reported apprehension, tension, fear, panic or worry. Possible scores are:
  • 5 Moderately Severe. Frequent, but not daily, periods of anxiety with autonomic accompaniment or some areas of functioning are disrupted by anxiety or worry. 6 - Severe. Anxiety with autonomic accompaniment daily but not persisting throughout the day or many areas of functioning are disrupted by anxiety or constant worry.
  • the inventors have determined that increases in the score of the BPRS item "anxiety" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "anxiety” impair psychological wellbeing, social support and management.
  • the aggregated score for the BPRS item "anxiety" across all 8 patients was 37 at base line. After 3 hours, it was reduced to 19 which corresponds to an improvement of 18 points or 49%. At day 1 after treatment, it was reduced to 16 which corresponds to an improvement of 21 points or 57%. At day 7 after treatment, it was reduced to 17 which corresponds to an improvement of 20 points or 54%.
  • the aggregated score for the BPRS item "anxiety" across all 4 patients was 25 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 14 points or 56%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of anxiety.
  • the reduction or elimination of anxiety is reflected by at least an improvement in the score of the BPRS item anxiety about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in anxiety as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of anxiety by treating a mental or nervous system disorder patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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 BPRS item “tension” relates to observable physical and motor manifestations of tension, "nervousness,” and agitation. Possible scores are
  • the inventors have determined that increases in the score of the BPRS item "tension" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "tension” impair mother-child interaction and psychological wellbeing.
  • the aggregated score for the BPRS item "tension" across all 8 patients was 16 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 5 points or 31 %. At day 1 after treatment, it was reduced to 11 which corresponds to an improvement of 5 points or 31 %. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 6 points or 38%.
  • the aggregated score for the BPRS item "tension" across all 4 patients was 14 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 5 points or 36%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%.
  • 5-MeO-DMT can be used to treat mental or nervous system disorder patients to achieve a reduction or elimination of tension.
  • the reduction or elimination of tension is reflected by at least an improvement in the score of the BPRS item tension about 2 hours; on day 1 , for instance, after about 24 hours; 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in tension as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the inventors furthermore conclude that a reduction or elimination of tension by treating a mental or nervous system disorder patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after about 24 hours; 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.
  • tension also affects other aspects of a mental or nervous system disorder, the inventors conclude that the observed improvement in the "tension" item on the BPRS will additionally contribute to an overall improvement in maternal functioning.
  • Improvements in one or more aspects of a mental or nervous system disorder will also lead to overall improvements.
  • treatment leads to a remission.
  • a remission of depressive symptoms may be reflected by a MADRS score equal to or less than 10 and occurs not later than about 2 hours; occurs on day 1 , for instance, after about 24 hours; 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.
  • a remission of depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurs not later than about 2 hours; occurs on day 1 , for instance, after about 24 hours; 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.
  • Improvements in maternal functioning include improvements in the functional domain of self-care. For instance, improvements in the MADRS items lassitude and/or reduced sleep lead to an increase in the BIMF scale scores reflecting self-care.
  • the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10 %, more preferably at least 20 %.
  • Improvements in maternal functioning include improvements in the functional domain of infant care. For instance, improvements in the MADRS items lassitude and/or concentration difficulties lead to an increase in the BIMF scale scores reflecting infant care.
  • the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15 %, more preferably at least 25 %.
  • Improvements in maternal functioning include improvements in the functional domain of mother-child interaction. For instance, improvements in the MADRS items inability to feel and inner tension lead to an increase in the Bl MF scale scores reflecting mother-child interaction.
  • the improvement of the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5 %, more preferably at least 15 %
  • Improvements in maternal functioning include improvements in the functional domain of psychological well-being. For instance, improvements in the MADRS items lassitude, pessimistic thoughts, inability to feel, inner tension and/or reduced sleep lead to an increase in the BIMF scale scores reflecting psychological well-being.
  • the improvement of the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25 %, more preferably at least 35 %.
  • Improvements in maternal functioning include improvements in the functional domain of social support. For instance, improvements in the MADRS item pessimistic thoughts leads to an increase in the Bl MF scale scores reflecting social support.
  • the improvement of the cumulative score of the BIMF scale items reflecting social support is preferably at least 10 %, more preferably at least 20 %
  • Improvements in maternal functioning include improvements in the functional domain of management. For instance, improvements in the MADRS items lassitude, pessimistic thoughts and/or concentration difficulties lead to an increase in the Bl MF scale scores reflecting management.
  • the improvement of the cumulative score of the Bl MF scale items reflecting management is preferably at least 20 %, more preferably at least 30 %
  • Improvements in maternal functioning include improvements in the functional domain of adjustment. For instance, improvements in the MADRS item lassitude leads to an increase in the BIMF scale scores reflecting adjustment.
  • the improvement of the cumulative score of the BIMF scale items reflecting adjustment is preferably at least 5 %, more preferably at least 15 %
  • the improvement in maternal functioning relates to one or more, in particular two or more functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
  • BIMF Barkin Index of Maternal Functioning
  • the Bl MF total score is improved by 10 % or more, preferably by 20 % or more.
  • Breastfeeding is the process of feeding human breast milk to a child. Breastfeeding includes feeding milk directly from the breast, as well as feeding the child with breast milk previously pumped and then bottle fed.
  • breastfeeding patients may be confronted with a situation where a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.
  • this decision will have a negative impact on maternal functioning and in particular compromise the functional domains mother-child interaction and psychological well-being.
  • the present invention also addresses the need for treating a mental or nervous system disorder in a breastfeeding mother without substantial interruption of breastfeeding.
  • breastfeeding can be resumed shortly after the treatment.
  • the inventors have investigated pharmacokinetic properties and metabolization of 5- MeO-DMT in an effort to determine from which point in time onwards after administration of 5-MeO-DMT or of a pharmaceutically acceptable salt breastfeeding is possible without exposing the suckling child to any relevant risk.
  • breast milk was obtained from a breastfeeding patient treated with 5-MeO- DMT for PPD.
  • a breastfeeding patient suffering from PPD received a dose of 6 mg 5-MeO-DMT and, after 1 hour, a further dose of 12 mg 5-MeO-DMT.
  • 5-MeO-DMT As regards the administered compound, 5-MeO-DMT, itself, absorption and distribution are rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing, for example, by inhalation or by injection.
  • Plasma protein binding is low (13-23 %).
  • the patient data obtained confirm the fast decrease of the 5-MeO-DMT concentration in breast milk (see Example 12). Measurement after 24 hours did not detect any 5-MeO- DMT.
  • RID Relative Infant Dose
  • the exposure of the infant can be determined.
  • a published estimate for daily intake of breast milk as a function of infant weight is 150 ml/kg/day.
  • an infant of 5 kg is fed three times over 24 hours, receiving 250 ml breast milk each time.
  • a 5-MeO-DMT concentration of 2167.0 pg/ml (the value determined at 1 hour) is assumed, for the second feed of 560.6 pg/ml (the value determined at 2.5 hours), and for the third feed of 42.1 pg/ml (the value determined at 8.5 hours).
  • the total exposure of the infant (Daily Infant Dosage, DID) is 692425 pg 5-MeO-DMT/day (0.000692425 mg/day), which value corresponds to 0.000138485 mg/kg/day.
  • the total dose is 18 mg (6 mg as the first dose and 12 mg as the second dose according to the uptitration scheme applied).
  • the amount actually delivered to the patient may be lower than the indicated dose, a calculation of the RID is also carried out assuming that the actually delivered amount is only 50 % of the indicated dose so that any a potential underestimation of the infant exposure is avoided.
  • RIDs Assuming a standard maternal weight of 60 kg, RIDs of 0.092 % (based on 9 mg as the maternal exposure) to 0.046 % (based on 18 mg as the maternal exposure) are obtained.
  • the accepted threshold for "low risk" RID is 10%. It is clear from the calculated value that the 5-MeO-DMT RID is significantly below this threshold.
  • reaction is catalysed by monoamine oxidase A (MAO-A).
  • the secondary amine, the primary amine and the aldehyde were not identified which indicates that they are not present at any time in a significant concentration.
  • the aldehyde intermediate metabolite undergoes 2 separate biotransformations in human liver hepatocytes. It is either oxidised to 5-methoxyindole acetic acid (5-MIAA) or reduced to 5-methoxyindole-3-ethanol.
  • 5-MIAA 5-methoxyindole acetic acid
  • Both resulting metabolites are endogenous substances and are formed in the human body, for instance, during synthesis and metabolism of melatonin and serotonin (see e.g. Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).
  • 5-MIAA has been identified as the major human metabolite.
  • 5-MIAA is considered to be a final metabolite of 5-MeO-DMT.
  • 5-MIAA shows relatively low plasma binding of -50% (mean fraction unbound (Fu); see the example section). It remains in circulation subject to renal clearance.
  • the 5-MIAA urine concentration determined after 2.5 hours of 12 980 501 pg/ml (about 12.98 mg/l) demonstrates that most of the 5-MIAA formed will be rapidly excreted.
  • 5-MIAA is rapid, pharmacokinetic data for healthy volunteers as well as for PPD patients indicate that small amounts of 5-MeO-DMT (corresponding to less than 10 % Cmax) may still be present after about 1 hour. In consequence, 5-MIAA will in fact be formed over some period of time after administration of 5- MeO-DMT.
  • 5-MIAA is a weak acid, which will be present in plasma in ionized form, which reduces the tendency of the compound to enter into breast milk.
  • a 5-MIAA concentration of 13945.2 pg/ml (the value determined at 1 hour) is assumed, for the second feed of 13240.9 pg/ml (the value determined at 2.5 hours), and for the third feed of 359.4 pg/ml (the value determined at 8.5 hours).
  • the total exposure of the infant (DID) is 0.00688638 mg 5-MIAA/day, which value corresponds to 0.00137728 mg/kg/day.
  • the maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO- DMT administered and the proportion of 5-MeO-DMT converted into 5-MIAA.
  • the mixture contains about 60 % 5- MIAA after 2 hours. Since metabolization is not complete, the actual proportion of 5- MeO-DMT converted into 5-MIAA will be higher. It can be assumed that more than 60 % up to close to 100 % of 5-MeO-DMT will be converted into 5-MIAA as the final metabolite, which is then excreted.
  • a total dose of 18 mg 5-MeO-DMT leads to between 10.15 mg 5-MIAA (60 % conversion) and 16.92 mg 5-MIAA (100 % conversion). Assuming as above that the delivered amount of 5-MeO-DMT is only 9 mg, between 5.08 mg 5-MIAA (60 % conversion) and 8.46 mg 5-MIAA (100 % conversion) is formed.
  • the maternal exposure will be between 0.085 mg/kg/day and 0.282 mg/kg/day. This leads to an estimate for the RID of between 0.49 % and 1 .62 %.
  • the accepted threshold for "low risk” RID is 10%, and it is clear from the calculated values, which represent conservative estimates, that the 5-MIAA RID is significantly below this threshold.
  • the risk profile for 5-MIAA is low considering not just the sub-threshold daily RID value but the fact that the compound is endogenously formed as a metabolite of certain naturally occurring tryptophane derivatives, such as serotonin.
  • levels of bufotenine, a primary metabolite of 5-MeO-DMT were assessed in urine, serum, and breast milk as described in Example 12. Notably, bufotenine was not detected in serum and breastmilk at any time point, and it was only detected in urine at the 2.5-hour timepoint (32.3 pg/ml). This data further demonstrates that bufotenine does not add to the risk profile for 5-MeO-DMT.
  • a further metabolite identified, bufotenine, is the result of O-demethylation, which is catalysed by CYP2D6.
  • the metabolized formed is then subject to glucuronidation, which is catalysed by UGT:
  • bufotenine (bufotenine glucuronide)
  • 5-MeO-DMT 5-MeO-DMT
  • Bufotenine glucuronide cannot bind to receptors and does not exert any effect. Moreover, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenine glucuronide is further converted to 5-hydroxyindole acetic acid:
  • 5-hydroxyindole acetic acid is an endogenous substance, for instance, it occurs in the metabolism of melatonin and serotonin (references as above).
  • the third metabolic pathway involves N-oxidation:
  • 5-MeO-DMT 5-MeO-DMT-N-oxide was deemed to be non-genotoxic in line with the negative in vitro genotoxicity assessment of the parent molecule.
  • the compound is water soluble and subject to rapid excretion, as confirmed by observations in the rat (Sitaram, B.R., Lockett, L., Blackman, G. L., McLeod, W. R., 1987.
  • breast feeding can be resumed shortly after the treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the treated mother may be advised to temporarily cease breastfeeding, for instance, for a certain time period or until a certain event.
  • Ceasing breastfeeding means that the infant is neither directly fed from the breast nor fed with breastmilk pumped when breastfeeding is discouraged.
  • Bottle feeding breastmilk obtained beforehand is, however, possible. It is the timepoint at which the breastmilk is expressed (and not when the child is fed) that is determinative.
  • the mother is advised to temporarily cease breastfeeding only for the period of the actual treatment, for instance, until the Clinical Assessment of Discharge Readiness (CADR) indicates discharge readiness.
  • the Clinical Assessment of Discharge Readiness (CADR) is carried out to determine that there are no clinical obstacles preventing the patient from returning home.
  • Discharge readiness according to the CADR requires finding that any adverse events are resolved or, if not resolved, are not preventing discharge; that the patient is fully orientated; that the patient has no hallucinations or perception distortions; that the patient is alert (responds readily to name spoken in normal tone; (Modified Observer’s Assessment of Alertness I Sedation scored as 5); that the vital signs are without clinically significant changes compared to baseline; and that the patient is discharge ready in the opinion of the treating physician.
  • the CADR may be administered about 1 hour after administration of the last dose.
  • a licensed professional may perform their own discharge readiness assessment on the basis of relevant factors such as patient vital signs and/or alertness/seda- tion.
  • the patient may be advised not to recommence breastfeeding before the later of discharge and 6 hours after the last dose; preferably the later of discharge and 3 hours after the last dose; more preferably the later of discharge and 2 hours after the last dose; in particular the later of discharge and 1 hour after the last dose.
  • breastfeeding may be temporarily ceased until the 5-MeO-DMT concentration in a breastmilk sample falls below 2000 pg/ml, 500 pg/ml or 75 pg/ml and/or until the 5-MIAA concentration in breastmilk falls below 14000 pg/ml, 2000 pg/ml or 75 pg/ml.
  • breastmilk may be pumped and discarded until the concentrations of 5- MeO-DMT and/or 5-MIAA fall below the indicated levels.
  • breastfeeding may be temporarily ceased for a fixed period, for instance, based on clinical experience regarding concentrations of 5-MeO-DMT and/or its metabolites in breastmilk.
  • the patient is advised to cease breastfeeding until 48 hours after receiving the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the patient is preferably advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, more preferably until 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • breastfeeding has to be interrupted for only 6 hours, even more preferably, for only 3 hours, in particular for only 2 hours and most preferably for only 1 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk is as low as possible, in order to avoid any relevant risk on the suckling child. Any relevant risk on the suckling child can be avoided, if any expressed breast milk is discarded as long as the concentrations of 5-MeO-DMT and/or 5-MIAA in breast milk exceed predetermined thresholds or breastfeeding is only resumed when the 5-MeO-DMT concentration and/or the 5-MIAA concentration in breast milk is below a predetermined threshold.
  • the threshold for 5-MeO-DMT in breast milk is as low as possible.
  • the threshold for 5-MIAA in breast milk is as low as possible.
  • the threshold for both, 5-MeO-DMT and 5- MIAA, in breast milk is as low as possible.
  • the Delivered Infant Dose (DID) for 5-MeO-DMT and/or 5-MIAA should be kept as low as possible.
  • the DID for 5-MeO-DMT is kept as low as possible.
  • the DID for 5-MIAA is kept as low as possible.
  • the DID for both, 5-MeO-DMT and 5-MIAA is kept as low as possible.
  • DID for 5-MeO-DMT and/or 5-MIAA of the invention are as follows:
  • breastfeeding needs adaption. This adaptation is selected from an appropriate time point for resumption of breastfeeding, an appropriate number of feeds during the first 24 hours after resumption of breastfeeding, by pumping and discarding breastmilk for an appropriate period of time or by a combination of these measures.
  • the Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA The Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA
  • the Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA should be as low as possible.
  • the RID for 5-MeO-DMT is kept as low as possible.
  • the RID for 5-MIAA is kept as low as possible.
  • the RID for both, 5-MeO-DMT and 5-MIAA is kept as low as possible.
  • RID for 5-MeO-DMT and/or 5-MIAA of the invention are as follows:
  • breastfeeding needs adaption. This adaptation is selected from an appropriate time point for resumption of breastfeeding, an appropriate number of feeds during the first 24 hours after resumption of breastfeeding, by pumping and discarding breastmilk for an appropriate period of time or by a combination of these measures.
  • DID Delivered Infant Dose
  • RID Relative Infant Dose
  • DID and the RID for 5-MeO-DMT and/or 5-MIAA are relevant aspects of the present invention. While each individual aspect is relevant as such, in a preferred embodiment of the invention both aspects, the DID for 5-MeO-DMT and/or 5-MIAA and the RID for 5-MeO-DMT and/or 5-MIAA, should be considered in combination. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and the RID for 5-MeO-DMT are combined.
  • the DID and the RID for 5-MeO-DMT is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MIAA and the RID for 5-MIAA are combined.
  • the DID and the RID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and the RID for 5-MIAA are combined.
  • the DID for 5-MeO-DMT and the RID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the RID for 5-MeO-DMT and the DID for 5-MIAA are combined.
  • the RID for 5-MeO-DMT and the DID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA are combined.
  • the DID for 5-MeO- DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention. Treatment of Mental or Nervous System Conditions
  • a depressive episode is a period of depressed mood and/or loss of pleasure in most activities.
  • a Major Depressive Episode is characterized by five or more symptoms that have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms being either (1) depressed mood or (2) loss of interest or pleasure.
  • the patient suffering from a Disorder Characterized by Depressive Episodes may suffer from a treatment resistant form of the disorder.
  • Depressive Episodes involve one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal and negative thinking.
  • Severity and treatment success can be assessed, for instance, by the Montgomery-As- berg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D).
  • MADRS Montgomery-As- berg Depression Rating Scale
  • HAM-D Hamilton Rating Scale for Depression
  • An improvement of the Disorder Characterized by Depressive Episodes is observed after about 2 hours; on day 1 , for instance after about 24 hours; 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.
  • An improvement of the Disorder Characterized by Depressive Episodes in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of the Disorder Characterized by Depressive Episodes, as reflected by a reduction in the CGI-S score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of the Disorder Characterized by Depressive Episodes is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of the Disorder Characterized by Depressive Episodes in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of the Disorder Characterized by Depressive Episodes, as reflected by a reduction in the MADRS score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of the Disorder Characterized by Depressive Episodes is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of the Disorder Characterized by Depressive Episodes in a patient, as reflected by a reduction in the HAM-D score, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of the Disorder Characterized by Depressive Episodes, as reflected by a reduction in the HAM-D score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning in a patient suffering from a Disorder Characterized by Depressive Episodes is reflected by at least an improvement in the Bl MF total score 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 maternal functioning in a patient suffering from a Disorder Characterized by Depressive Episodes occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the Bl MF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • MDD Major Depressive Disorder
  • the patient may suffer from moderate or severe MDD as indicated by a Montgomery- Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 17 or more. It is further considered that the patient may suffers from severe major depressive disorder as indicated by a Montgom- ery-Asberg Depression Rating Scale (MADRS) score of 35 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 25 or more.
  • MADRS Montgomery- Asberg Depression Rating Scale
  • HAM-D Hamilton Depression Rating Scale
  • the patient suffering from MDD may suffer from a treatment resistant form of the disorder (TRD).
  • TRD treatment resistant form of the disorder
  • MDD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal and negative thinking.
  • Severity and treatment success can be assessed, for instance, by the Montgomery-As- berg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D).
  • MADRS Montgomery-As- berg Depression Rating Scale
  • HAM-D Hamilton Rating Scale for Depression
  • An improvement of MDD is observed after about 2 hours; on day 1 , for instance after about 24 hours; 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.
  • An improvement of MDD in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of MDD, as reflected by a reduction in the CGI-S score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of MDD is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of MDD in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of MDD, as reflected by a reduction in the MADRS score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of MDD, as reflected by a reduction in the HAM-D score, is observed on day 1 , for instance after about 24 hours; 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 maternal functioning in a patient suffering from MDD is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from MDD occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the BIMF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Persistent Depressive Disorder also referred to as dysthymia
  • dysthymia is a chronic form of depression. It is diagnosed if depression is present for most of the day for the majority of days over at least a two-year period. Any symptom-free period is less than 2 months.
  • the patient 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.
  • Severity and treatment success can be assessed, for instance, by the Montgomery-As- berg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D).
  • MADRS Montgomery-As- berg Depression Rating Scale
  • HAM-D Hamilton Rating Scale for Depression
  • Persistent Depressive Disorder In patients suffering from Persistent Depressive Disorder altered functional connectivity is observed within and/or between several brain regions implicated in processing, regulation, emotional memory; cognitive processes related to rumination; impaired concentration and physiological arousal. Dysfunctional connectivity is observed within and/or between the DMN, salience network, executive control network and limbic network. Functional connectivity differs significantly from that observed in healthy controls. Treating a patient suffering from Persistent Depressive Disorder, including a treatment resistant form of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof leads to an improvement of the Persistent Depressive Disorder.
  • Persistent Depressive Disorder is observed after about 2 hours; on day 1 , for instance after about 24 hours; 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.
  • An improvement of Persistent Depressive Disorder in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Persistent Depressive Disorder, as reflected by a reduction in the CGI-S score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Persistent Depressive Disorder is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of Persistent Depressive Disorder in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Persistent Depressive Disorder, as reflected by a reduction in the MADRS score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Persistent Depressive Disorder is observed on day 1 , for instance after about 24 hours; 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 maternal functioning in a patient suffering from Persistent Depressive Disorder is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from Persistent Depressive Disorder occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the Bl MF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Seasonal Affective Disorder is a mood disorder with seasonal pattern, with symptoms often beginning in autumn and remitting in spring. Many people experience sadness, hopelessness, a loss of interest in activities, tiredness, and social withdrawal.
  • the patient 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.
  • Severity and treatment success can be assessed, for instance, by the Montgomery-As- berg Depression Rating Scale (MADRS) or the Hamilton Rating Scale for Depression (HAM-D).
  • MADRS Montgomery-As- berg Depression Rating Scale
  • HAM-D Hamilton Rating Scale for Depression
  • An improvement of Seasonal Affective Disorder is observed after about 2 hours; on day 1 , for instance after about 24 hours; 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.
  • An improvement of Seasonal Affective Disorder in a patient occurs not later than about 2 hours after the last administration of 5- MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Seasonal Affective Disorder, as reflected by a reduction in the CGI-S score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Seasonal Affective Disorder is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of Seasonal Affective Disorder in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Seasonal Affective Disorder, as reflected by a reduction in the MADRS score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Seasonal Affective Disorder is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of Seasonal Affective Disorder in a patient, as reflected by a reduction in the HAM-D score, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of Seasonal Affective Disorder as reflected by a reduction in the HAM-D score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning in a patient suffering from Seasonal Affective Disorder is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from Seasonal Affective Disorder occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the BIMF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • BD Bipolar Disorder
  • Major depressive episodes emotional lows
  • highs manic or hypomanic episodes
  • BD is a recurrent chronic disorder that affects more than 1% of the world’s population irrespective of ethnic origin or socioeconomic status.
  • the patient suffering from BD may suffer from a treatment resistant form of the disorder.
  • Bipolar I Disorder if there has been at least one manic episode, with or without depressive episodes. It is classified as Bipolar II Disorder if there has been at least one hypomanic episode (but no full manic episodes) and one major depressive episode. If these symptoms are due to drugs or medical problems, they are not diagnosed as Bipolar Disorder.
  • the patient suffering from BD whether diagnosed with Bipolar II Disorder or with Bipolar I Disorder, in particular suffers from a current major depressive episode.
  • the severity of a current major depressive episode may be assessed using the Mont- gomery-Asberg Depression Rating Scale (MADRS).
  • MADRS Mont- gomery-Asberg Depression Rating Scale
  • the patient may have a total score of equal to or greater than 19, such as greater or equal than 24, in particular greater or equal than 37.
  • the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater or equal than 24, in particular greater or equal than 37.
  • BDRS Bipolar Depression Rating Scale
  • BD involves one or more of sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social/emotional withdrawal and negative thinking.
  • Severity and treatment success can be assessed, for instance, by the Montgomery-As- berg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAM-D) or the Bipolar Depression Rating Scale (BDRS).
  • MADRS Montgomery-As- berg Depression Rating Scale
  • HAM-D Hamilton Rating Scale for Depression
  • BDRS Bipolar Depression Rating Scale
  • the BDRS is designed to measure the severity of depressive symptoms in bipolar depression.
  • the BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and/or mixed symptoms expressed by patients currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms.
  • the scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.
  • the questions address depressed mood; sleep disturbance; appetite disturbance; reduced social engagement; reduced energy and activity; reduced motivation; impaired concentration and memory; anxiety; anhedonia; affective flattening; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation.
  • An improvement of BD is observed after about 2 hours; on day 1 , for instance after about 24 hours; 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.
  • An improvement of BD in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of BD as reflected by a reduction in the CGI-S score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of BD is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of BD in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of BD as reflected by a reduction in the MADRS score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO- DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of BD is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of BD is observed on day 1 , for instance after about 24 hours; 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.
  • An improvement of BD in a patient occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An improvement of BD as reflected by a reduction in the BDRS score, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning in a patient suffering from BD is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from BD occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the BIMF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • An Anxiety Disorder is a type of mental health condition. Symptoms include feelings of nervousness, panic and fear as well as sweating and a rapid heartbeat. Anxiety involves a complex cognitive, affective, physiological, and behavioural response system associated with preparation for anticipated events or circumstances perceived as threatening.
  • An Anxiety Disorder also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal and negative thinking.
  • the patient suffering from an Anxiety Disorder may suffer from a treatment resistant form of the disorder.
  • the severity of an Anxiety Disorder can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety”.
  • BAI Beck Anxiety Inventory
  • HAM-A Hamilton Anxiety Rating Scale
  • Psychic Anxiety subscale of the HAM-A sum of items 1-6 and 14
  • the Anxious Mood item of the HAM-A item 1
  • BPRS Brief Psychiatric Rating Scale
  • Anxiety Disorders are moreover associated with suicidal ideation.
  • C-SSRS Columbia Suicide Severity Rating Scale
  • Anxiety disorders are studied by functional magnetic resonance imaging. In general, all anxiety disorders show abnormalities in the default mode network (DMN). Further networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting state balance within and/or between each of these networks, e.g., SMN and SN, relative to the DMN may be abnormal in the different anxiety disorders.
  • DNN default mode network
  • SN salience network
  • SSN sensorimotor network
  • the resting state balance within and/or between each of these networks, e.g., SMN and SN, relative to the DMN may be abnormal in the different anxiety disorders.
  • T reating a patient suffering from an Anxiety Disorder including a treatment resistant form for the Disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.
  • the reduction or elimination of anxiety in a patient suffering from an Anxiety Disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety in a patient suffering from an Anxiety Disorder occurs not 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 persists until at least 6 days; in particular until at least 14 days; 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 an Anxiety Disorder, including a treatment resistant form of the Disorder is reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 clinical response in a patient suffering from an Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by an at least 50% decrease of the HAM-A score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • a remission of anxiety in a patient suffering from such an Anxiety Disorder, including a treatment resistant form 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 , for instance after about 24 hours; 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 remission of anxiety in a patient suffering from such an Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by a HAM-A score of 7 or less preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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 an Anxiety Disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety, as reflected by a decrease of the score of the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14), preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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 an Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the Anxious Mood item of the HAM-A (item 1), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety, as reflected by a decrease of the score of the Anxious Mood item of the HAM-A (item 1) preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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 an Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the BPRS item "anxiety" is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety in a patient suffering from an Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the BPRS item "anxiety”, occurs not 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 of the score of the BPRS item "anxiety”, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • T resting a patient suffering from an Anxiety Disorder, including a treatment resistant form of the Disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.
  • the reduction or elimination of suicidal ideation in a patient suffering from an Anxiety Disorder, including a treatment resistant form of the Disorder, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 suicidal ideation in a patient suffering from an Anxiety Disorder, including a treatment resistant form of the Disorder occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the reduction or elimination of suicidal ideation preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Anxiety Disorders generally, including the specific conditions discussed in detail below as well as anxiety disorder due to a medical condition, which occurs when a medical condition causes extreme fear, anxiety, or panic; other specified anxiety disorder, which may be diagnosed if a patients has most but not all of the criteria for an anxiety disorder; and unspecified anxiety disorder; which is often diagnosed if a patient experiences anxiety or panic but there is a lack of information to make a complete diagnosis of another anxiety disorder.
  • the improvement of maternal functioning in a patient suffering from an Anxiety Disorder is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from an Anxiety Disorder occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the BIMF total score, preferably persists until at least 14 days; 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 an excessive anxiety regarding separation from home and/or from someone to whom the patient has a strong emotional attachment.
  • Anxiety Disorder also involves one or more of sleep disturbance, cognitive dysfunction, social/emotional withdrawal and negative thinking.
  • a patient suffering from Separation Anxiety Disorder may suffer from a treatment resistant form of the disorder.
  • the severity of Separation Anxiety Disorder can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety”.
  • BAI Beck Anxiety Inventory
  • HAM-A Hamilton Anxiety Rating Scale
  • Psychic Anxiety subscale of the HAM-A sum of items 1-6 and 14
  • the Anxious Mood item of the HAM-A item 1
  • BPRS Brief Psychiatric Rating Scale
  • C-SSRS Columbia Suicide Severity Rating Scale
  • Anxiety Disorder disorders are studied by functional magnetic resonance imaging. In general, all anxiety disorders show abnormalities in the default mode network (DMN). Further networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting state balance within and/or between each of these networks, e.g., SMN and SN, relative to the DMN may be abnormal in the different anxiety disorders.
  • DNN default mode network
  • SN salience network
  • SSN sensorimotor network
  • the resting state balance within and/or between each of these networks, e.g., SMN and SN, relative to the DMN may be abnormal in the different anxiety disorders.
  • Treating a patient suffering from Separation Anxiety Disorder including a treatment resistant form for the Disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.
  • the reduction or elimination of anxiety in a patient suffering from Separation Anxiety Disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety in a patient suffering from Separation Anxiety Disorder occurs not 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 persists until at least 6 days; in particular until at least 14 days; 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 a treatment resistant form of the Disorder is reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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.
  • a clinical response in a patient suffering from Separation Anxiety Disorder including a treatment resistant form of the Disorder, as reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the clinical response in a patient suffering from Separation Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by an at least 50% decrease of the HAM-A score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • a remission of anxiety in a patient suffering from such Separation Anxiety Disorder, including a treatment resistant form 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 , for instance after about 24 hours; 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.
  • a remission of anxiety in a patient suffering from such Separation Anxiety Disorder occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the remission of anxiety in a patient suffering from such Separation Anxiety Disorder including a treatment resistant form of the disorder, as reflected by a HAM-A score of 7 or less, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety, as reflected by a decrease of the score of the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14), preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the Anxious Mood item of the HAM-A (item 1), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety, as reflected by a decrease of the score of the Anxious Mood item of the HAM-A (item 1) preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 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, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the BPRS item "anxiety" is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety in a patient suffering from Separation Anxiety Disorder, including a treatment resistant form of the Disorder, as reflected by a decrease of the score of the BPRS item "anxiety”, occurs not 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 of the score of the BPRS item "anxiety”, preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Treating a patient suffering from Separation Anxiety Disorder including a treatment resistant form of the Disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.
  • the reduction or elimination of suicidal ideation in a patient suffering from Separation Anxiety Disorder, including a treatment resistant form of the Disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 suicidal ideation in a patient suffering from Separation Anxiety Disorder, including a treatment resistant form of the Disorder occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the reduction or elimination of suicidal ideation preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning in a patient suffering from Separation Disorder is reflected by at least an improvement in the BIMF total score 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 maternal functioning in a patient suffering from Separation Disorder occurs not later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the improvement of maternal functioning as reflected by an improvement in the BIMF total score, preferably persists until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • Agoraphobia is a fear of situations or places that may cause feelings of panic, entrapment, helplessness, or embarrassment.
  • a patient suffering from Agoraphobia may have difficulty leaving the house.
  • the thought of leaving the house may cause considerable anxiety to the point of avoidance.
  • Fears of crowds, traveling, elevators, movie theatres, malls, etc. might cause significant challenges.
  • Agoraphobia also involves one or more of sleep disturbance, cognitive dysfunction, so- cial/emotional withdrawal and negative thinking.
  • a patient suffering from Agoraphobia may suffer from a treatment resistant form of the disorder.
  • the severity of Agoraphobia can be assessed by using the Beck Anxiety Inventory (BAI). It can also be assessed by using the Hamilton Anxiety Rating Scale (HAM-A); the Psychic Anxiety subscale of the HAM-A (sum of items 1-6 and 14); the Anxious Mood item of the HAM-A (item 1); the Brief Psychiatric Rating Scale (BPRS) item "anxiety”.
  • BAI Beck Anxiety Inventory
  • HAM-A Hamilton Anxiety Rating Scale
  • Psychic Anxiety subscale of the HAM-A sum of items 1-6 and 14
  • the Anxious Mood item of the HAM-A item 1
  • BPRS Brief Psychiatric Rating Scale
  • C-SSRS Columbia Suicide Severity Rating Scale
  • Functional magnetic resonance imaging in individuals suffering from Agoraphobia reveals alterations in functional connectivity within and/or between resting-state networks involved in Anxiety. Treating a patient suffering from Agoraphobia, including a treatment resistant form for the Disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.
  • the reduction or elimination of anxiety in a patient suffering from Agoraphobia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 anxiety in a patient suffering from Agoraphobia occurs not 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 persists until at least 6 days; in particular until at least 14 days; 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 Agoraphobia, including a treatment resistant form of the Disorder is reflected by an at least 50% decrease of the HAM-A score, compared to the respective score prior to treatment, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 , for instance after about 24 hours; 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 clinical response in a patient suffering from Agoraphobia, including a treatment resistant form of the Disorder, as reflected by an at least 50% decrease of the HAM- A score preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • a remission of anxiety in a patient suffering from such Agoraphobia, including a treatment resistant form 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 , for instance after about 24 hours; 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 remission of anxiety in a patient suffering from such Agoraphobia, including a treatment resistant form of the Disorder, as reflected by a HAM- A score of 7 or less preferably persists until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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Abstract

5-Méthoxy-N, N-diméthyltryptamine (5-MeO-DMT) ou un sel pharmaceutiquement acceptable de celle-ci pour une utilisation dans le traitement d'un trouble mental ou du système nerveux chez une mère ayant un enfant de 18 mois ou moins, la 5-MeO-DMT ou un sel pharmaceutiquement acceptable de celle-ci étant administrée par voie intraveineuse, intramusculaire ou sous-cutanée.
PCT/EP2023/076819 2023-01-30 2023-09-27 Traitement de troubles mentaux Ceased WO2024160391A1 (fr)

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IL322427A IL322427A (en) 2023-01-30 2023-09-27 Treatment of mental disorders
AU2023427992A AU2023427992A1 (en) 2023-01-30 2023-09-27 Treatment of mental disorders
CN202380094304.6A CN120641095A (zh) 2023-01-30 2023-09-27 精神障碍的治疗
KR1020257028947A KR20250138805A (ko) 2023-01-30 2023-09-27 정신 장애의 치료
MX2025008749A MX2025008749A (es) 2023-01-30 2025-07-25 Tratamiento de trastornos mentales

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PCT/EP2023/057885 WO2023186837A1 (fr) 2022-03-27 2023-03-27 Traitement de la depression post-partum
PCT/EP2023/057874 WO2023186827A1 (fr) 2022-03-27 2023-03-27 5-méthoxy-n, n-diméthyltryptamine pour le traitement de la dépression post-partum
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US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12275735B2 (en) 2021-01-15 2025-04-15 Beckley Psytech Limited Ergoline analogues

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12275735B2 (en) 2021-01-15 2025-04-15 Beckley Psytech Limited Ergoline analogues
US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12246005B2 (en) 2023-06-13 2025-03-11 Beckley Psytech Limited 5-methoxy-n,n-dimethyltryptamine (5-MeO-DMT) formulations

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