5-MEO-DTM for treatment of bipolar affective disorders

Abstract

5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof is used for the treatment of a patient diagnosed as having bipolar affective disorders wherein the 5-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.

Description

Technical Field

[0001] The present invention relates to an improved method for treating bipolar disorder (BD), comprising administering a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof to a patient in need thereof. The treatment improves not only depressive mood, but also particularly improves characteristic aspects of BD, such as sleep disturbance, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social / emotional withdrawal or alienation (anhedonia, emotional withdrawal, and emotional apathy).

[0002] The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).

[0003] Treatment according to the invention reduces or eliminates the risk of treatment-induced mania or hypomania. Background Art

[0004] Bipolar disorder is a mental health condition characterized by dramatic mood swings, including low moods (major depressive episodes) and high moods (manic or hypomanic episodes). Bipolar disorder is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0005] Symptoms that indicate a depressive episode include depressed mood, such as feeling sad, empty, hopeless, or tearful; marked loss of interest or pleasure in all or almost all activities; significant weight loss, weight gain, or decreased or increased appetite when not dieting; insomnia or excessive sleeping; restlessness or sluggish behavior; fatigue or low energy; feelings of worthlessness or excessive or inappropriate guilt; decreased ability to think or concentrate, or indecisiveness; and thinking about, planning, or attempting suicide.

[0006] A major depressive episode typically includes five or more of these symptoms. It includes symptoms severe enough to cause significant difficulty in daily situations, such as work, school, social activities, or relationships.

[0007] During a manic or hypomanic episode, people appear or feel unusually energetic, happy, or irritable, and they often make impulsive decisions with little thought to the consequences. The need for sleep is also usually decreased.

[0008] If the elevated mood is severe or accompanied by psychosis, it is called mania; if it is less severe, it is called hypomania. Hypomania does not involve psychotic symptoms.

[0009] In bipolar disorder, periods of depression and periods of elevated mood can each last from a few days to a few weeks. Episodes of mood swings can occur infrequently or many times a year.

[0010] Bipolar disorder was previously known as manic-depressive illness. However, it has long been recognized that this condition is distinct from major depressive disorder. DSM-III (Diagnostic and Statistical Manual of Mental Disorders III; 1980) first formally separated bipolar disorder (BD) with mania from non-bipolar major depressive disorder (MDD).

[0011] If at least one manic episode occurs (with or without a depressive episode), BD is classified as bipolar I. If at least one hypomanic episode (but not a full manic episode) and one major depressive episode occur, it is classified as bipolar II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

[0012] Hypomania is a milder form of mania, and bipolar II disorder is not a milder form of bipolar I. A 13.6-year study of the natural course of bipolar II disorder found that patients were symptomatic during 53.9% of the follow-up weeks, with depressive symptoms occurring during 50.3% of the follow-up weeks (Judd, L., Akiskal, H., Schettler, P., Coryell, W., Endicott, J., Maser, J., Solomon, D., Leon, A., and Keller, M., 2003. A Prospective Investigation of the Natural History of the Long-term Weekly Symptomatic Status of Bipolar II Disorder. Archives of General Psychiatry, 60(3), p. 261). A similar study of patients with bipolar I disorder found that patients were symptomatic during 47.3% of the follow-up weeks, with depressive symptoms accounting for 31.9% of the follow-up weeks (Judd, L., Akiskal, H., Schettler, P., Endicott, J., Maser, J., Solomon, D., Leon, A., Rice, J., and Keller, M., 2002. The Long-term Natural History of the Weekly Symptomatic Status of Bipolar I Disorder. Archives of General Psychiatry, 59(6), p. 530). It is therefore clear that depressive symptoms dominate the symptomatic state of both types of bipolar disorder - most prominently in bipolar II disorder. Evidence suggests that a greater proportion of patients with bipolar II disorder attempt suicide (Karanti, A., Kardell, M., Joas, E., Runeson, B., E. and Landén, M., 2019. Characteristics of bipolar I and II disorders: A study of 8766 individuals. Bipolar Disorders, 22(4), pp. 392-400).

[0013] In most cases, bipolar disorder is treated with medication and psychological counseling (psychotherapy). However, current treatments have had only limited success, for example, due to often limited or unsustainable treatment responses, late onset of responses, side effects that limit long-term medication administration, and inconvenient dosing regimens that often limit patient compliance.

[0014] The evidence for or against the use of antidepressants in patients with BD remains highly inconsistent (Baldessarini 2020) and a recent national study found that 54.9% of patients with bipolar II disorder were receiving antidepressant medication (Karanti, Kardell et al. 2020). This is despite the fact that several reports have shown that patients with BD may experience clinical worsening when treated with antidepressants, exhibiting symptoms such as agitation, insomnia, anger and irritability, and are at increased risk of suicidal behavior (Baldessarini 2020). Treatment-induced mania or hypomania (TEM) is a significant risk associated with such treatment.

[0015] Although there are many treatment options available for BD in addition to antidepressants, many of them are associated with adverse effects. Quetiapine, approved for the acute treatment of depressive episodes in bipolar I and bipolar II, is associated with weight gain, dry mouth, sedation, excessive sleep, and dizziness – leading to high rates of discontinuation due to adverse reactions in patients receiving quetiapine in placebo-controlled trials (Calabrese, Keck et al. 2005, Thase, Macfadden et al. 2006, Suppes, Datto et al. 2010). In addition, quetiapine is typically titrated over a period of time spanning multiple days, resulting in a delayed onset of action. Studies have shown that lurasidone results in a higher incidence of nausea and extrapyramidal events compared to placebo (Loebel, Cucchiaro et al. 2014, Loebel, Cucchiaro et al. 2014). Furthermore, olanzapine and the olanzapine-fluoxetine combination can lead to excessive sleeping and weight gain (Tohen, Vieta et al. 2003).

[0016] Even in treated BD, depression as the primary psychopathology is associated not only with excess morbidity but also with mortality due to co-occurring general medical disorders. The risk of medical disorders including diabetes or metabolic syndrome and cardiovascular disorders and the associated mortality are several times higher than in the general population or in patients with other psychiatric disorders.

[0017] Furthermore, the normalized mortality rate for suicide in BD is 20 times higher than the mortality rate in the general population and exceeds the mortality rate for other major psychiatric disorders.

[0018] The current state of BD treatment efficacy is aptly summarized by Baldessarini et al:

[0019] “All available pharmacological treatments for bipolar depression have limited efficacy and carry the risk of adverse metabolic or neurologic effects.”

[0020] Therefore, new treatments for BD represent a significant unmet medical need.

[0021] While there has been a recent surge of interest in the use of hallucinogens to treat psychiatric disorders, this has not led to treatments for BD to date. This is due to a general lack of clinical data to allow conclusions to be drawn about the clinical utility of hallucinogens in BD, and also because of particular concerns that hallucinogens may actually worsen the illness, particularly by inducing mania or hypomania.

[0022] Hallucinogens, including LSD, are chemical compounds, some naturally occurring and some synthetic, which are defined by their ability to induce distortions of the senses, such as changes in auditory and visual perception, as well as distortions of mood and cognition, after ingestion. The term hallucinogen covers a fairly broad group of psychoactive molecules with different modes of action. Some psychiatric disorders are in principle considered amenable to treatment with psychoactive molecules, such as LSD.

[0023] However, no psychedelic drug has yet been approved by any regulatory agency. In fact, clinical experience with such molecules is still quite limited.

[0024] One compound that has been studied in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020 / 169850 reports on tests on healthy volunteers and clinical trials involving patients with treatment-resistant depression (TRD), a form of major depressive disorder.

[0025] In this context, it is an object of the present invention in particular to provide more effective therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) an earlier onset of clinical response, and / or d) a more durable clinical response) than previously described therapies, as well as dosing regimens and routes of administration for such therapies.

[0026] It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens and routes of administration for such therapies, which have better safety and / or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens and routes of administration for such therapies, which are more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens and routes of administration for such therapies, which are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. It is a further object of the present invention to determine specific disease aspects and subgroups of specific disease aspects that can benefit from such improved psychoactive therapies. Summary of the invention

[0027] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients diagnosed with bipolar disorder.

[0028] Patients may be diagnosed as having bipolar II disorder or as having bipolar I disorder. Patients treated will typically be suffering from a current major depressive episode. Patients may have been treated previously without success.

[0029] In the context of the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous administration.

[0030] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience. A dose of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt thereof may be administered.

[0031] Treatment success can be assessed using a variety of rating scales, including but not limited to the Bipolar Depression Rating Scale (BDRS), the Montgomery-Asberg The MADRS and CGI-S scales were used to assess the severity of depression.

[0032] A clinical response (reflected, for example, by a decrease in Clinical Global Impression-Severity (CGI-S) score) generally occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response is observed on day 1, for example, after about 24 hours.

[0033] For the treatment of sleep disorders, a clinical response (reflected, for example, by a decrease in CGI-S score) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0034] The clinical response preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0035] Patients did not experience treatment-induced mania or hypomania.

[0036] Treatment specifically results in improvement in at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social / emotional withdrawal or alienation.

[0037] In addition, treatment reduces or eliminates suicidal thoughts.

[0038] It also reduces or eliminates at least one of the psychotic symptoms; irritability; instability; increased motor drive; increased speech; and agitation. DETAILED DESCRIPTION

[0039] definition

[0040] As used in the context of the present invention, unless otherwise indicated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT will also generally be used. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated based on the weight of the free base, assuming the use of equimolar amounts.

[0041] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional as suffering from a bipolar disorder, such as bipolar disorder type II, in accordance with generally accepted medical practice. For example, the diagnosis may be made in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association. The diagnosis will be made by a physician or psychologist. It is not sufficient for the human subject to believe that he or she suffers from the disorder.

[0042] As used in the context of the present invention, "suicidal ideation" means thinking about, considering, or planning to commit suicide. A doctor or psychologist will diagnose a patient for the presence of suicidal ideation using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they suffer from suicidal ideation. In some cases, a patient with suicidal ideation will be at risk for imminent suicide, or will be considered to have "suicidal intent."

[0043] As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, illness or disorder, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, illness or disorder.

[0044] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human being that is being sought by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0045] "Clinical response" includes, but is not limited to, improvements on rating scales. These scales assess various disease aspects. Scales that can be used according to the present invention include the Brief Psychiatric Rating Scale (BPRS), the Bipolar Depression Rating Scale (BDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the 17-item Hamilton Depression Rating Scale (HAM-D). Other related scales for assessing clinical outcomes include the Young's Mania Rating Scale (YMRS), the Clinically Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Columbia Suicide Severity Rating Scale (C-SSRS).

[0046] Clinical response can also be assessed based on the Clinical Global Impression-Severity scale (CGI-S), the Patient Global Impression-Severity scale (PGI-S), the Clinical Global Impression-Improvement scale (CGI-I), or the Patient Global Impression-Improvement scale (PGI-I).

[0047] Individual items of the scales indicated as well as subcombinations of individual items can be used to assess specific disease aspects.

[0048] When clinical response is assessed at an early time point after drug administration (e.g., 2 hours), such endpoints can be reasonably modified based on endpoints developed for longer recall periods (e.g., MADRS is typically 7 days) (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration). This also applies to the BDRS (particularly the sleep disturbance items) and any other scale used in this article, unless a recall period is specifically specified.

[0049] The considerations outlined apply to early time points because, on the one hand, in order to assess clinical response, the influence of the patient's pre-treatment status on any scores recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0050] At a later time point, such as on day 1 or later, all items of the relevant scales used to assess clinical response can generally be assessed, using an appropriate recall period (if necessary), so that no pre-treatment scores need to be carried forward.

[0051] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-rating questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

[0052] Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. The 19 items are divided into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

[0053] Each component is scored from 0 to 3. Higher scores indicate more severe sleep disturbance. A detailed scoring description of the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213.

[0054] The seven component scores are then summed to create an overall score ranging from 0-21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas, or moderate difficulty in more than three areas.

[0055] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

[0056] The Verbal Recognition Memory (VRM) test assesses verbal memory and new learning. It measures the ability to encode and subsequently retrieve verbal information. During this task, 18 words are displayed on the screen and participants are subsequently asked to recall these words in a free recall phase. This is followed by a recognition test, in which participants are presented with 36 words (including target words and distractors) and asked to answer "yes" or "no" as to whether they have seen the word before. After a 20-minute delay period, another recognition test follows, this time using a new set of distractor words. Administration time is approximately 6 minutes (including immediate and delayed recall).

[0057] The rapid visual processing (RVP) test is a sensitive tool for assessing sustained attention. A white box is displayed in the center of the screen, within which single numbers from 2 to 9 appear in a pseudo-random order at a rate of 100 numbers per minute on the screen. The patient must detect a series of target sequences (e.g., 3-5-7, 2-4-6, and 4-6-8) and touch a button when the last number of the target sequence is seen. Nine target sequences appear at 100 numbers per minute. The task duration is approximately 7 minutes.

[0058] Spatial working memory (SWM) tasks require the retention and manipulation of visual-spatial information. This self-ordered test provides a measure of strategy as well as working memory errors. The test involves multiple colored squares (boxes) displayed on a screen, which requires the selection of strategies to fill in the empty columns. The test takes about 4 minutes to complete. Outcome measures of SWM include errors and strategies. The computerized Corsi Block will be the version of the SWM task used in this study.

[0059] The digit symbol substitution task (DSST) is a version of the original paper-pencil task taken from the Wechsler Adult Intelligence Scale (Royer, FL and Janowitch, L., 1973. Performance of process and reactive schizophrenics on a symbol-digit substitution task. Percept Mot Skills 37(1):63-70). The patient is presented with a coding scheme consisting of a row of squares at the top of the screen, in which nine digits are randomly associated with specific symbols. The same symbols are presented in a fixed order at the bottom of the screen as a row of individual response buttons. The randomization process is chosen so that the symbols never appear in the same ordinal position within the two rows. The coding scheme and response buttons remain visible while the patient is presented with a series of single digits in the center of the screen. The task is to match each digit with a symbol from the coding list and then click the corresponding response button. The number of correctly coded digits within 3 minutes is the performance measure.

[0060] Treatment outcomes are assessed by using one or more indices or scales at one or more time points after completion of the course of treatment.

[0061] The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is about 2 to 3 hours after the last administration. The assessment can be performed, for example, about 2 hours or about 3 hours after the last administration.

[0062] If more than one index or scale is administered, it cannot be done simultaneously. Thus, while one index or scale may be administered about 2 hours after the last administration of 5-MeO-DMT, another index or scale may be administered, for example, about 3 hours after the last administration of 5-MeO-DMT. It is contemplated herein that assessments performed at two time points, or generally within a time frame of about 2 to 3 hours, are equally reflective of early treatment outcomes.

[0063] Evaluation on day 1 or day 1 means evaluation on the second day after administration. Evaluation will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. Evaluation can be performed after about 24 hours.

[0064] Assessment on or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

[0065] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. The active compound is administered by intravenous administration, intramuscular administration or subcutaneous administration.

[0066] As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined order of one or more separate administrations.

[0067] Bipolar disorder

[0068] Bipolar disorder is characterized by a variety of symptoms and has various facets.

[0069] The primary psychopathology is depression, and the presentation of a patient going through a depressive phase may initially lead to the patient being diagnosed as suffering from major depressive disorder (MDD). However, even in the depressive phase, BD has a variety of features that define it as distinct from the former.

[0070] Of particular interest here are the symptoms that are more strongly associated with BD than with other psychiatric disorders, as these are indicators of how patients are evaluated for treatment. Although many symptoms can be said to span multiple disorders, considerable work has been done to identify several symptoms that are strongly present in patients with BD: sleep disturbances, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and emotional flattening). Characteristic symptoms also include suicidal ideation. In addition, characteristic symptoms include mixed symptoms (psychotic symptoms; irritability; instability; increased motor drive; increased verbalization; agitation).

[0071] Clinical assessment tools for BD, such as the Bipolar Depression Rating Scale (BDRS), have been developed and validated that take these symptoms into account.

[0072] Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. BDRS has been verified by trained assessors and can be used in clinical practice. According to clinical interviews, BDRS project assessments the severity of depression and / or mixed symptoms that patients currently and over the past few days have shown. If the current symptoms are inconsistent with the symptoms of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the highest possible score is 60. The higher the score, the higher the severity.

[0073] The problems addressed are: depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

[0074] Each of these aspects was evaluated and assigned a score of 0, 1, 2, or 3.

[0075] Depressed mood was scored as 0 if there was no self-reported and / or observed depression, as evidenced by feelings of gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) if there were brief or transient periods of depression, or mild depressed mood; 2 (moderate) if depressed mood was evident but not persistent and other emotions were expressed, or if the intensity of depression was moderate; and 3 (severe) if depressed mood was pervasive or persistent but of significant intensity.

[0076] Sleep disturbance (sleep disorder) is assessed based on the variation in the total amount of sleep during a 24-hour period, independent of external factors. It can manifest as insomnia (reduced total sleep time) or hypersomnia (increased total sleep time, including daytime sleepiness).

[0077] Insomnia was rated as 0 (no reduction in total sleep time); 1 (mild; reduction of up to 2 hours); 2 (moderate; 2-4 hours); and 3 (severe; more than 4 hours).

[0078] Alternative ratings of excessive sleep include 0 (no increase in total sleep time, including daytime sleep); 1 (mild; less than 2 hours, or normal amount but non-restorative); 2 (moderate; 2-4 hours); and 3 (severe; more than 4 hours).

[0079] Appetite disturbances are assessed based on changes in appetite and food consumption, independent of external factors. They can manifest as either a loss of appetite or an increase in appetite.

[0080] Loss of appetite was rated as 0 (no change in appetite or food consumption); 1 (mild; no change in food intake, but must force oneself to eat or reports food has no taste); 2 (moderate; some decrease in food intake); and 3 (significant decrease in food intake, with almost no food eaten).

[0081] Alternative ratings of increased appetite include 0 (no change in appetite or food consumption); 1 (mild; no change in food intake, but increased hunger); 2 (moderate; some increase in food intake, e.g., comfort eating); and 3 (marked increase in food intake or cravings).

[0082] Decreased social engagement was scored as 0 if there was no subjective report of decreased social and interpersonal engagement or interaction; 1 (mild) if social engagement was slightly reduced but social or interpersonal functioning was not impaired; 2 (moderate) if social engagement was markedly reduced with some functional sequelae, such as avoidance of some social engagements or conversations; and 3 (severe) if social interactions were markedly reduced or there was avoidance of almost all forms of social contact, such as refusing to answer phone calls or see friends or family.

[0083] Decreased energy and activity was scored as 0 if there was a decrease in energy, drive, or goal-directed behavior; 1 (mild) if the patient was able to perform usual activities but with increased effort; 2 (moderate) if energy was markedly reduced, resulting in a decrease in some specific role activities; and 3 (severe) if there was leaden paralysis or cessation of nearly all specific role activities (eg, spending excessive time in bed, avoiding telephone calls, poor personal hygiene).

[0084] Decreased motivation was scored as 0 if there was no report of a subjective decrease in drive, motivation, and consequent goal-directed activity; 1 (mild) if motivation was slightly reduced but functioning was not reduced; 2 (moderate) if motivation or drive was reduced and volitional activity was markedly reduced or great effort was required to maintain usual levels of functioning; and 3 (severe) if motivation or drive was reduced to the point where goal-directed behavior or functioning was markedly reduced.

[0085] If there is no subjective report of decreased attention, concentration, or memory, and no consequent functional impairment, the score for impaired concentration and memory is 0; if attention, concentration, or memory is slightly impaired but there is no functional impairment, the score is 1 (mild); if attention, concentration, or memory is severely impaired or forgetful with some functional impairment, the score is 2 (moderate); if concentration or memory is significantly impaired with significant functional impairment (e.g., inability to read or watch TV), the score is 3 (severe).

[0086] Anxiety was scored as 0 if there was no subjective report of worry, tension, and / or physical anxiety symptoms (e.g., tremors, palpitations, dizziness, vertigo, tingling, sweating, dyspnea, butterflies in the stomach, or diarrhea); 1 (mild; brief worry or tension over trivial matters); 2 (moderate; severe anxiety, tension, or worry, or some accompanying physical features); and 3 (severe; marked and persistent anxiety, tension, or worry that interferes with normal activities; or panic attacks).

[0087] Anhedonia was scored as 0 (no subjective reduction in the ability to experience pleasure in usual activities); 1 (mild; slightly reduced pleasure from normally pleasurable activities); 2 (moderate; markedly reduced pleasure from normally pleasurable activities; some retention of pleasure from isolated activities); or 3 (severe; complete inability to experience pleasure).

[0088] Affective apathy is scored as 0 if there is no subjective perception of a decrease in the intensity or range of feelings or emotions; 1 (mild) if there is a slight decrease in the range of emotions, or a temporary decrease in the range or intensity of feelings; 2 (moderate) if there is a significant decrease in the range or intensity of feelings, but some emotions are retained, such as an inability to cry; and 3 (severe) if there is a marked and pervasive decrease in the range of emotions, or an inability to experience usual emotions.

[0089] Feelings of worthlessness (also referred to simply as worthlessness) were scored as 0 (no subjective feelings or thoughts of self-worth or decreased self-worth); 1 (mild; slightly decreased self-worth); 2 (moderate; some feelings of worthlessness and thoughts of decreased self-worth); and 3 (severe; marked, pervasive, or persistent feelings of worthlessness, e.g., feeling that others would be better off without you, inability to appreciate positive qualities).

[0090] Feelings of helplessness and hopelessness (also referred to simply as helplessness and hopelessness) characterize a subjective feeling of pessimism or depression about the future, inability to cope, or a feeling of loss of control. If absent, the score is 0. If the feeling of being unable to cope as usual or pessimism occurs occasionally and is mild, the score is 1 (mild); if the patient often feels unable to cope, or has a significant feeling of helplessness or hopelessness, but sometimes disappears, the score is 2 (moderate); if there is a significant and persistent feeling of pessimism, helplessness, or hopelessness, the score is 3 (severe).

[0091] Suicidal ideation is related to thoughts or feelings that life is worthless, thoughts about death, or suicide, and is scored as 0 if there are no such thoughts; 1 (mild) if there are thoughts that life is worthless or meaningless; 2 (moderate) if there are thoughts about dying or death but no active suicidal thoughts or plans; and 3 (severe) if there are suicidal thoughts or plans.

[0092] Feelings of guilt (also referred to simply as feelings of guilt) were scored as 0 if there were no subjective feelings of self-blame, failure, or regret for past real or imagined mistakes; 1 (mild) if there was a slight decrease in self-esteem or increased self-criticism; 2 (moderate) if there were clear thoughts of failure, self-criticism, inability to cope, or rumination about past failures and their impact on others, with an ability to recognize excesses; and 3 (severe) if there was a clear, pervasive, or persistent feeling of guilt, such as feeling like one should be punished; or if there was no clear recognition of excesses.

[0093] If there are no overvalued thoughts, delusions, or hallucinations, the score for psychotic symptoms is 0; if there are mild overvalued thoughts, such as self-criticism or pessimism, but no obvious impact on behavior, the score is 1 (mild); if there are significant overvalued thoughts and a clear impact on behavior, such as strong feelings of guilt and clear beliefs that others would be better off without them, the score is 2 (moderate); if there are obvious psychotic symptoms, such as delusions or hallucinations, the score is 3 (severe).

[0094] Irritability reported atypical subjective irritability, short temper, and easy anger, manifested by verbal or physical outbursts, and was scored as 0 if there was none; 1 (mild) if there was mild subjective irritability, which might not be very obvious; 2 (moderate) if verbal impatience and irritability were clearly observed during the interview; and 3 (severe) if physical outbursts were reported, such as throwing / breaking objects, or obvious abusive verbal outbursts.

[0095] If no mood lability was observed or mood swings were reported, the instability score was 0. If the subjective report of mood lability was mildly increased, it was scored as 1 (mild); if mood lability was clearly observed, it was scored as 2 (moderate); if mood lability was obvious and dominant, and mood swings were frequent or intense, it was scored as 3 (severe).

[0096] Increased exercise drive involves subjective reports and objective evidence of increased drive to exercise and motor activity. If exercise drive is normal, it is scored as 0; if drive is slightly increased but not observable during the interview, it is scored as 1 (mild); if the increase in energy and drive is significant and observable, it is scored as 2 (moderate); if the increase in drive is marked or persistent, it is scored as 3 (severe).

[0097] Increased speech involves the observation of an increase in the rate or volume of speech, or the observation of racing thoughts. This item is scored as 0 if no such observations are made; 1 (mild) if there is a slight increase in the rate or volume of speech; 2 (moderate) if thoughts are racing, or the patient is noticeably more talkative, noticeably easily distracted, or there is some verbosity, which does not interfere with the interview; and 3 (severe) if the racing thoughts interfere with the interview.

[0098] Agitation was scored as 0 if no fidgeting or agitation was observed, 1 (mild) if there was mild fidgeting, 2 (moderate) if there was a marked increase in agitation, and 3 (severe) if there was marked agitation, such as almost continuous pacing or hand-wringing.

[0099] Although higher scores on the BDRS scale indicate more severe illness, there are no universally accepted cutoffs for when a patient is considered moderately or severely ill. The BDRS score range used in this article to represent the severity of depressive episodes in patients with bipolar disorder is: 13-18 as "mildly ill," 19-23 as "moderately ill," 24-36 as "somewhat ill," 37-39 as "severely ill," and ≥40 as "extremely ill."

[0100] Various other scales are also available to assess disease severity and clinical outcomes of treatment.

[0101] The CGI was developed to provide a brief, independent assessment of the clinician's perception of a patient's global functioning before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0102] The CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is the patient currently?” Rated on a seven-point scale: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat severely ill; 6 = severely ill; and 7 = the sickest patient.

[0103] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0104] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, there is only one inquiry rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

[0105] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI). It consists of one item based on the CGI and adapted for the patient. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0106] The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, SA and Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p. 382). It is designed as an adjunct to the Hamilton Depression Rating Scale (HAM-D) and is more sensitive to changes brought about by antidepressants and other forms of treatment. The higher the MADRS score, the more severe the depression. The items considered are obvious sadness; reported sadness; inner tension; decreased sleep; decreased appetite; difficulty concentrating; laziness; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60. The score range used in this article to assess the severity of depressive episodes in patients with bipolar disorder is: 13-18 for "mild illness", 19-23 for "moderate illness", 24-36 for "severe illness", 37-39 for "severe illness", and ≥40 for "extremely severe illness" (Thase, 2021).

[0107] Using a structured interview guide (SIGMA) for MADRS will improve the reliability of a given scale (Williams, JBW and Kobak, KA, 2008. Development and reliability of a structured interview guide for the Montgomery Asberg Depression Rating Scale (SIGMA). The British Journal of Psychiatry 192, p. 52; Freeman, MP, Pooley, J., Flynn, MJ, Baer, ​​L., Mischoulon, D., Mou, D. and Fava, M., 2017. Guarding the Gate. Remote Structured Assessments to Enhance Enrollment Precision in Depression Trials. Journal of Clinical Pharmacology 37(2), p. 176).

[0108] The Hamilton Depression Rating Scale (Ham-D) is a clinician-administered depression assessment scale. The original version contained 17 items (HDRS17) that addressed depressive symptoms (Hamilton, M., 1960. A Rating Scale for Depression, J Neurol Neurosurg Psychiatry 23:56–62; Hamilton, M., 1967. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6(4):278–96). Although the scale was designed to be completed after an unstructured clinical interview, a semistructured interview guide is now also available (Williams, JB, 1988. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 45(8):742–7). The subsequent 21-item version includes 4 items designed to subtype depression.

[0109] The Young Mania Rating Scale (YMRS; Young, RC, Biggs, JT, Ziegler, VE and Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. The British journal of psychiatry, 133 (5), 429-435) is one of the most commonly used rating scales for assessing manic symptoms. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the past 48 hours. Additional information is based on clinical observations made during the clinical interview. Items are selected based on published descriptions of core symptoms of mania. The YMRS follows the style of the HAM-D, with severity ratings given to each item. Four items are rated on a scale of 0 to 8 (irritability, speech, thought content, and destructive / aggressive behavior), while the remaining seven items are rated on a scale of 0 to 4. These four items are given twice the weight of the other items to compensate for the lack of cooperation of seriously ill patients. Each severity level has clearly described anchor points. Once experience with the scale is gained, the authors encourage the use of full-scale or half-scale ratings. The scale is typically completed by a clinician or other rater who is trained and has expertise in working with patients with mania.

[0110] Brief Psychiatric Rating Scale (BPRS) is designed to screen psychotic symptoms in a structured manner. The scale is one of the most widely used scales for measuring psychotic symptoms and was first published in 1962. The design was later updated. The most commonly used version today includes 18 different fields for doctors or psychologists to evaluate (in general, JE and Gorham, DR, 1962. The brief psychiatric rating scale. Psychological Reports 10, page 799; in general, JE and Gorham, DR, 1988. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacology Bulletin 22, page 97).

[0111] Eighteen items (somatic focus, anxiety, emotional withdrawal, conceptual confusion, guilt, tension, mannerisms and posture, grandiosity, depressed mood, hostility, suspiciousness, hallucinatory behavior, bradykinesia, uncooperativeness, unusual thought content, blunted affect, excitement, and disorientation) were scored, and each item was rated on a scale of 1-7.

[0112] The doctor or psychologist will complete two tasks during the approximately 15-minute interview with the patient:

[0113] · They will ask the patient a series of questions from a list.

[0114] They will check to see if the patient exhibits certain behaviors.

[0115] Based on the answers and observed behaviors, the physician or psychologist will complete the BPRS form by ranking the severity of each domain using a scale of one to seven: one means no sign or symptom is present, and seven means the sign or symptom is present and at a severe level. If a specific sign or symptom cannot be rated, a score of 0 or "not assessed" is recorded.

[0116] The Clinically Administered Dissociative States Scale (CADSS) is assessed by the researcher through interviews with the patients. The CADSS is a 27-item scale with 19 subject-rated items and 8 observer-rated items. The rating range is 0 "not at all" to 4 "extremely" (Bremner, JD, Krystal, JH, Putnam, FW, Southwick, SM, Marmar, C., Charney, DS and Mazure, CM, 1998. Measurement of Dissociative States with the Clinician-Administered Dissociative States Scale (CADSS). Journal of Traumatic Stress 11 (1), p. 125).

[0117] The CADSS is divided into 3 components: 1) Depersonalization, 2) Derealization, and 3) Amnesia. These subscales are summed together to form a total dissociation score. The CADSS was specifically designed to serve as a standardized measure of current state dissociative symptomatology.

[0118] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a detailed questionnaire that assesses suicidal behavior and ideation to help identify the need for immediate medical intervention and to provide data for an overall assessment of the effectiveness of treatments related to suicidality. The C-SSRS is evidence-based and is part of national and international public health initiatives involving the assessment of suicidality (Posner, K., Brown, G.K., Stanley, B., Brent, D.A., Yershova, K.V., Oquendo, M.A., Currier, G.W., Melvin, G.A., Greenhill, L., Shen, S., and Mann, J.J., 2011. The Columbia–Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. American Journal of Psychiatry 168(12), pp. 1266–77).

[0119] The questionnaire will be administered in the form of an interview by a registered psychologist or medical doctor.

[0120] The present invention provides for the treatment of patients diagnosed with bipolar disorder, especially bipolar disorder type II, as defined herein, and in particular patients diagnosed with bipolar disorder suffering from a current major depressive episode. The treatment includes in particular the treatment of the above-mentioned aspects of the disease, namely sleep disturbances, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory) and social / emotional withdrawal or alienation (anhedonia, emotional withdrawal and emotional apathy).

[0121] The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased verbalization; agitation).

[0122] The present invention specifically provides for the treatment of depression in BD patients without inducing hypomania or mania.

[0123] Active Agent

[0124] The above discussion shows that BD is characterized by several aspects, which in themselves carry a significant disease burden and require appropriate treatment. Therefore, treatments are needed not only to improve the overall disease score (especially through pharmacological interventions), but also to improve specific aspects of the disease.

[0125] The inventors believe that carefully selected hallucinogens may lead to improved treatment of important aspects of BD, and may result in overall improvement of the disease.

[0126] A group of hallucinogens consists of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often called "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

[0127] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, of which the indoleamines are divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

[0128] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-associated receptors.

[0129] Recently published studies on the use of serotonergic psychedelics such as LSD, psilocybin, and DMT (the shamanic medicine ayahuasca) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may preclude their use in the treatment of BD patients.

[0130] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138 (11): 1508-9) reported a patient who had a manic episode after taking LSD or an LSD analog. The patient had symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23 (4): 1-3) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a man with bipolar disorder who switched to mania after consuming ayahuasca, a beverage containing DMT.

[0131] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49 (4), 294-296.

[0132] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, especially in the treatment of BD patients, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

[0133] The inventors have determined that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug of particular interest for the treatment of bipolar disorder and various aspects thereof. 5-MeO-DMT has unique pharmacological properties that are different from other psychedelic drug compounds.

[0134] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype than other classic psychedelics.

[0135] As further detailed in the Examples section below, the inhibition constants (K) for psilocin (the dephosphorylated form of psilocybin formed following ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin dephosphate, DMT, and 5-MeO-DMT at the 5-HT2A receptor in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while dephosphopsilin and DMT exhibit moderate affinity. i values) were 37, 117, and 122 nM, respectively. Thus, dephosphorylated psilocybin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0136] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

[0137] 5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0138] Compared to other psychedelics (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing a significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

[0139] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0140] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

[0141] Further, it has been reported that antidepressants induce isolated hypomanic events in patients suffering from treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of inducing hypomania.

[0142] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to, for example, several hours with oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0143] Specifically, the default mode network (Default Mode Network), one of several RSNs, is associated with a variety of psychiatric disorders, and abnormal connections in these disorders have been confirmed by functional MRI. This has been noted in bipolar disorder (Chai et al. 2011, Wang et al. 2016), although combined with a variety of distinctive connection patterns and / or cortical limbic connections (e.g., between the prefrontal cortex and the amygdala (de Almeida 2009)) between several other RSNs (Rai, 2021), this seems to distinguish bipolar depression from unipolar depression. Although the involvement of DMN and other RSNs in bipolarity may be different from that in unipolarity, the presence of abnormal connections combined with the improvements observed in BD-related symptoms and the absence of induction of manic episodes in recent clinical trials allow the inventors to conclude that 5-MeO-DMT is suitable for treating bipolar disorder, especially when administered as described herein.

[0144] Various aspects of bipolar disorder, such as sleep disturbance, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social / emotional withdrawal or alienation (anhedonia, emotional withdrawal, and emotional flattening) can be improved. Additional aspects of the disorder that 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.

[0145] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be administered to BD patients using the dosing regimen and administration route as described herein without a significant risk of inducing mania or hypomania.

[0146] In addition, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [ 3 H]LSD and serotonin to estimate nonspecific binding and determine Ki It is 2.3nM.

[0147] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0148] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0149] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0150] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0151] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0152] The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

[0153] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social / emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

[0154] Another characteristic of 5-MeO-DMT is its short half-life.

[0155] 5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0156] The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0157] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0158] The properties of 5-MeO-DMT make the compound particularly suitable for treating BD, such as bipolar disorder type II, especially for patients suffering from a current major depressive episode.

[0159] The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

[0160] According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used.When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0161] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0162] A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

[0163] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0164] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

[0165] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

[0166] Methods for the preparation of these compounds are known in the art.

[0167] Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0168] Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

[0169] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

[0170] In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0171] An example of a suitable organic moiety is 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 , where R 1 , R 2 , R 3 and R 4 Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

[0172] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 , R 3 and R 4 As defined above.

[0173] Prodrugs, especially prodrugs of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0174] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0175] Methods for preparing prodrugs as discussed herein are known in the art.

[0176] According to the present invention, the T of the metabolite 5-MeO-DMT measured after oral administration of the prodrug at 10 mg / kg in male Sprague-Dawley (SD) rats max The value is preferably 1 hour or less, more preferably 0.7 hour or less, particularly 0.5 hour or less.

[0177] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0178] patient

[0179] Patients treated according to the present invention are diagnosed as suffering from bipolar disorder by licensed professionals according to generally accepted medical practices. For example, the diagnosis can be made according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association.

[0180] In one aspect, the patient is diagnosed with bipolar disorder type II. In another aspect, the patient is diagnosed with bipolar disorder type I.

[0181] Typically, people diagnosed with either bipolar II or bipolar I are experiencing a current major depressive episode.

[0182] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score equal to or greater than 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0183] Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0184] Further alternatively or additionally, the patient may have a Hamilton Depression Rating Scale (HAM-D) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0185] The patient may suffer from a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. The patient has not adequately improved after at least two adequate courses of treatment, in particular, wherein at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy. In particular, at least two previous courses of treatment were administered during the current depressive episode.

[0186] Patients with a major depressive episode treated in accordance with the present invention will typically have a Young Mania Rating Scale (YMRS) total score of 8 or less.

[0187] Treatment for BD

[0188] As indicated above, treatment according to the present invention relates to various aspects of bipolar disorder.

[0189] These include sleep disturbances, psychomotor retardation (decreased energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and affective flattening).

[0190] The treatment also counteracted suicidal ideation. In addition, the treatment also improved mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased verbalization; agitation).

[0191] Treatment of patients suffering from bipolar disorder according to the present invention will generally involve more than one of the above aspects. Treatment will generally result in a clinical response in several or all of the above aspects with an overall improvement.

[0192] According to the invention, the above aspects can also be treated if they occur independently of bipolar disorder, for example in the context of a different psychiatric disorder. A clinical response can be achieved regardless of whether the patient has been diagnosed with bipolar disorder.

[0193] Treatment according to the invention alleviates or eliminates (or improves or eliminates) one aspect of the disease. As used herein, this means that if the aspect is assessed on the BDRS scale, there is at least one point of improvement (mitigation) or the patient is in complete remission (elimination) after treatment, i.e. the corresponding aspect score is 0.

[0194] If the domain is assessed on the MADRS scale, there is an improvement of at least one point (reduction) or the patient is in complete remission (elimination) after treatment, i.e. the corresponding domain score is 0.

[0195] If the aspect is assessed according to the BPRS scale, there is at least one point improvement (reduction) or the patient is completely relieved (eliminated) after treatment, that is, the corresponding aspect score is 1.

[0196] The clinical response can also be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and / or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and / or to 0 points.

[0197] To further support the clinical utility of 5-MeO-DMT in patients suffering from BD, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in aspects of the disease that are also commonly observed in patients suffering from bipolar disorder. The inventors particularly noted improvements in various symptoms and combinations of symptoms that are unique to BD.

[0198] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) Although TRD is a distinct disorder from BD, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for BD.

[0199] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

[0200] The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate therapeutic efficacy through improvements in overall MADRS scores, the inventors focused on the items that make up the various rating scales and noted overlap between several of these sub-scoring items and the symptoms outlined above, which is particularly noteworthy in BD patients. Multiple patients in the recruited cohort showed significant improvements in one or more of these sub-scoring items, a result that confirms the inventors' findings that 5-MeO-DMT is a compound suitable for treating BD patients, particularly BD patients who experience these symptoms.

[0201] The specific sub-scoring items in each scale are identified in more detail below. While these items do not always provide an exact match to the BD-related symptoms outlined above, the inventors recognize that there is overlap between these items and those symptoms and conclude that improvements noted for these items will translate to improvements for related symptoms that have been specifically included in BD-specific assessment scales, such as the BDRS. Indeed, given the level of support in the literature for the association of these symptoms with BD, the inventors conclude that efficacy in treating one or more of these symptoms will result in significant improvements in the overall outcome of BD patients treated with 5-MeO-DMT.

[0202] One aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is sleep disturbance. 5-MeO-DMT can be administered to BD patients to improve the patient's sleep quality.

[0203] Sleep disturbances, including changes in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities, are particularly noted in patients with bipolar disorder, as described by Kaplan et al., Gottlieb et al., and others.

[0204] Further studies have shown that the default mode network (DMN) is associated with sleep disruption (De Havas et al.; Nie et al.). The inventors believe that the association between the DMN and sleep disruption and the effects of 5-MeO-DMT on the DMN after appropriate administration and dosing suggest that sleep disorders may be treated with 5-MeO-DMT.

[0205] In the clinical studies mentioned above involving the administration of 5-MeO-DMT, the MADRS item "sleep reduction" reflecting insomnia was evaluated, among others.

[0206] The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the normal pattern of the subject's own health. When the subject's sleep is normal, the score is 0. A score of 2 reflects mild difficulty falling asleep, or slightly reduced, shallow or intermittent sleep time. A score of 4 means that sleep time is reduced or interrupted by at least two hours. A score of 6 means less than two or three hours of sleep.

[0207] In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

[0208] In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0209] Thus, the score of the scale item "sleep reduction" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance in patients, especially patients suffering from psychiatric disorders such as BD.

[0210] Thus, according to the present invention, treating a patient suffering from a sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorder.

[0211] Reduction or elimination of sleep disturbances can be reflected as an improvement in the score of the BDRS item Sleep Disturbance on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0212] The reduction or elimination of sleep disturbance (reflected by an improvement in the score of the BDRS item sleep disturbance) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbance (reflected by an improvement in the score of the BDRS item sleep disturbance) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0213] If the sleep disturbance is sleep loss, the reduction or elimination of the sleep disturbance can be reflected in at least an improvement in the score of the MADRS item sleep loss on day 1, e.g., 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.

[0214] The reduction or elimination of sleep disturbances (reflected as an improvement in the score of the MADRS item sleep reduction) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances (reflected as an improvement in the score of the MADRS item sleep reduction) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0215] If the patient suffers from sleep disturbance, improvement in sleep disturbance is reflected in a decrease in Clinical Global Impression-Severity (CGI-S) score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0216] Improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0217] Improvement in sleep disturbances (as reflected by a score of at least "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0218] The improvement in sleep disturbance (reflected by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0219] As mentioned above, sleep disturbance is an item of BDRS. Since sleep disturbance also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "sleep reduction" item on MADRS will not only bring about an associated improvement in the score of the "sleep disturbance" BDRS scale item, but also promote an overall improvement in the BDRS score.

[0220] If the patient suffers from sleep disturbances, reduction or elimination of sleep disturbances is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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, wherein the recall period spans from the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point.

[0221] If the patient suffers from sleep disturbance, then the reduction or elimination of sleep disturbance (reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period spans from the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point. The reduction or elimination of sleep disturbance (reflected by an improvement in the PSQI score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0222] Another aspect of bipolar disorder (especially bipolar II disorder) that can be treated by administering 5-MeO-DMT is psychomotor retardation, that is, a combination of decreased energy and activity and decreased motivation. Psychomotor retardation involves a slowing of the individual's thinking and decreased physical movement. Impaired psychomotor function may result in a significant slowing of physical and emotional responses. Psychomotor retardation has been noted in patients suffering from bipolar disorder. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's psychomotor retardation, that is, to counteract decreased energy and activity and decreased motivation.

[0223] In the clinical study mentioned above involving the administration of 5-MeO-DMT, the MADRS item "sluggishness" was assessed, among others.

[0224] "Sloth" means difficulty or slowness in initiating and performing daily activities.

[0225] A score of 0 means starting with almost no difficulty and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and cannot do anything without help, the score is 6.

[0226] This MADRS scale item is particularly relevant to psychomotor retardation (ie, decreased energy and activity and decreased motivation).

[0227] In the study group that received the individualized dosing regimen, the total score for the MADRS item "slouching" for all eight patients was 27 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 17 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 22 points or 81%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 24 points or 89%.

[0228] In the 12 mg group, the total score of the MADRS item "slouching" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 6 points or 38%. On the first day after treatment, the score dropped to 0, which corresponds to an improvement of 16 points or 100%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

[0229] Thus, the score of the scale item "sloth" which is particularly relevant to psychomotor retardation was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat psychomotor retardation in patients, especially those suffering from psychotic disorders such as BD, i.e. to combat decreased energy and activity and decreased motivation.

[0230] Thus, according to the present invention, treatment of a patient suffering from psychomotor retardation reduces or eliminates psychomotor retardation. Treatment improves or eliminates decreased energy and activity and / or decreased motivation.

[0231] Reduction or elimination of psychomotor retardation can be reflected as an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0232] The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the BDRS items reduced energy and activity and / or reduced motivation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the BDRS items reduced energy and activity and / or reduced motivation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0233] Alternatively or additionally, reduction or elimination of psychomotor retardation may be reflected as an improvement in the score of the MADRS item lazyness at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0234] The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the MADRS item lazy) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation (reflected by an improvement in the score of the MADRS item lazy) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0235] If the patient suffers from psychomotor retardation, improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14 and / or on day 28.

[0236] Improvement in psychomotor retardation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0237] Improvement in psychomotor retardation (reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0238] The improvement in psychomotor retardation (reflected by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0239] As mentioned above, "reduced energy and activity" and "reduced motivation" are items of BDRS. Since psychomotor retardation also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "laziness" item on MADRS will not only bring about a related improvement in the score of the "reduced energy and activity" and / or "reduced motivation" BDRS scale items, but also contribute to the overall improvement of the BDRS score.

[0240] Another aspect of bipolar disorder (particularly bipolar II disorder) that can be treated by administering 5-MeO-DMT is negative thinking, including feelings of worthlessness; feelings of helplessness and hopelessness; and feelings of guilt. 5-MeO-DMT can be administered to BD patients to reduce or eliminate such symptoms in the patients.

[0241] Symptoms such as pessimism, feelings of worthlessness, and feelings of helplessness and hopelessness have been noted in patients with bipolar disorder. In addition, BD patients have been reported to be more prone to morbid, excessive, or inappropriate guilt than MDD patients.

[0242] These symptoms are collectively referred to as negative thinking in this article.

[0243] A MADRS scale item that is particularly relevant to this aspect of BD is “pessimistic thoughts,” which represents thoughts of guilt, low self-esteem, self-condemnation, sin, regret, and destructiveness.

[0244] If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score refers to persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of destruction, regret, or irreparable guilt and absurd and unshakable self-blame, the score is 6.

[0245] In the study group that received the individualized dosing regimen, the total score for the MADRS item "pessimistic thoughts" for all eight patients was 28 at baseline. After 2 hours, the score dropped to 7, which corresponds to an improvement of 21 points or 75%. On the first day after treatment, the score dropped to 4, which corresponds to an improvement of 24 points or 86%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 25 points or 89%.

[0246] In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

[0247] The BPRS item that is particularly relevant to guilt is "Guilt Feelings." This item is related to excessive concern or regret about past behavior. Possible ratings are:

[0248] 1- No guilt.

[0249] 2 - Very Mild. Worries about disappointing someone or failing at something, but is not distracted. Can easily shift thoughts to other things.

[0250] 3-Mild. Worry about disappointing someone or failing at something and tends to be distracted. Tends to express guilt to others.

[0251] 4 - Moderate. Obsessively dwells on guilt, wrongdoing, or hurting others by something they did or did not do, but can easily shift their focus to other things.

[0252] 5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something; can shift focus to other things but only with great effort. Not delusional.

[0253] 6 - Severe. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. Moderate absent-mindedness present.

[0254] 7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on the delusion.

[0255] In the study group that received the individualized dosing regimen, the total score for the BPRS item "guilt" was 34 at baseline for all eight patients. After 3 hours, the score dropped to 14, which corresponds to an improvement of 20 points or 59%. On the first day after treatment, the score dropped to 11, which corresponds to an improvement of 23 points or 68%. On the seventh day after treatment, the score dropped to 10, which corresponds to an improvement of 24 points or 71%.

[0256] In the 12 mg group, the total score of the BPRS item "guilt" for all 4 patients was 18 at baseline. After 3 hours, the score dropped to 9, which corresponds to an improvement of 9 points or 50%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%.

[0257] Thus, the score of the MADRS scale item "pessimistic thoughts" which is particularly related to negative thinking was significantly improved, and the score of the BPRS item "guilt" was also significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat negative thinking in patients, especially patients suffering from mental illnesses such as BD.

[0258] Thus, according to the present invention, treatment of a patient suffering from negative thinking reduces or eliminates the negative thinking. Treatment reduces or eliminates feelings of worthlessness; feelings of helplessness and hopelessness; and / or feelings of guilt.

[0259] A reduction or elimination of negative thoughts can be reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0260] The reduction or elimination of negative thoughts (reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected by an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0261] Alternatively or additionally, reduction or elimination of negative thoughts may be reflected as an improvement in the score of the MADRS item pessimistic thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0262] The reduction or elimination of negative thoughts (reflected as an improvement in the score of the MADRS item pessimistic thoughts) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected as an improvement in the score of the MADRS item pessimistic thoughts) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0263] Alternatively or additionally, reduction or elimination of negative thoughts may be reflected in an improvement in the score of the BPRS item guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0264] The reduction or elimination of negative thoughts (reflected by an improvement in the score of the BPRS item Guilt) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of negative thoughts (reflected by an improvement in the score of the BPRS item Guilt) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0265] If the patient suffers from negative thinking, improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14 and / or on day 28.

[0266] Improvement in negative thinking, as reflected at least by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0267] Improvement in negative thinking (assessed by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0268] The improvement in negative thinking (reflected by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0269] As mentioned above, helplessness and hopelessness; worthlessness; and guilt are all items of the BDRS. Since negative thinking also affects other aspects of BD in addition, the inventors concluded that the observed improvements in the scores of the "pessimistic thoughts" item on the MADRS and the "guilt" item on the BPRS will not only bring about related improvements in the scores of the "worthlessness", "helplessness and hopelessness" and / or "guilt" BDRS scale items, but also promote the overall improvement of the BDRS score. For example, the BDRS item "psychotic symptoms" includes strong guilt as a contributing factor.

[0270] Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's anxiety.

[0271] The BPRS item that is particularly relevant to anxiety is "Anxiety." This item is related to reported worry, nervousness, fear, panic, or concern. Possible scores are

[0272] 1- No Anxiety

[0273] 2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

[0274] 3 - Mild. Frequent worrying but able to easily shift attention to other things.

[0275] 4-Moderate. Worried most of the time and unable to easily redirect attention, but functioning is not impaired; or anxious occasionally with autonomic symptoms, but functioning is not impaired.

[0276] 5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms or some areas of functioning are disrupted by anxiety or worry.

[0277] 6 - Severe. Anxiety is daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

[0278] 7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

[0279] In the study group that received the individualized dosing regimen, the total score for the BPRS item "Anxiety" for all eight patients was 37 at baseline. After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points or 54%.

[0280] In the 12 mg group, the total score of the BPRS item "anxiety" for all 4 patients was 25 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 14 points or 56%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%.

[0281] The inventors concluded that 5-MeO-DMT could be used to treat anxiety in patients, particularly those suffering from psychiatric disorders such as BD.

[0282] Thus, according to the present invention, treatment of a patient suffering from anxiety reduces or eliminates the anxiety.

[0283] Reduction or elimination of anxiety can be reflected as an improvement in the BDRS item anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours later; on day 7; on day 14; and / or on day 28.

[0284] The reduction or elimination of anxiety (reflected as an improvement in the BDRS item anxiety) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected as an improvement in the BDRS item anxiety) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0285] Alternatively or additionally, reduction or elimination of anxiety is reflected in at least an improvement in BPRS item anxiety at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0286] The reduction or elimination of anxiety (reflected in an improvement in the BPRS item anxiety) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety (reflected in an improvement in the BPRS item anxiety) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0287] If the patient suffers from anxiety, improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0288] Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0289] Improvement in anxiety (as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0290] The improvement in anxiety (reflected by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0291] As mentioned above, "anxiety" is an item of BDRS. Since anxiety also affects other aspects of BD, the inventors concluded that the observed improvement of the "anxiety" item on BPRS will not only bring about a related improvement of the "anxiety" BDRS scale item, but also promote an overall improvement in the BDRS score.

[0292] Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's cognitive dysfunction, particularly difficulty concentrating.

[0293] Patients with bipolar depression show impairments in the areas of memory and executive function, with evidence suggesting that bipolar depressed subjects have poorer executive functioning compared with unipolar depressed subjects. In addition, psychomotor retardation has been reported to be accompanied by a cognitive component in bipolar patients.

[0294] A MADRS item that is particularly relevant to impairments in concentration and memory is “difficulty concentrating.”

[0295] This item represents difficulty organizing thoughts, escalating to inability to concentrate. If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty collecting personal thoughts, the score is 2. If there is difficulty concentrating and maintaining thoughts, resulting in reduced ability to read or have a conversation, the score is 4. If the patient cannot read or talk easily, the score is 6.

[0296] In the study group that received the individualized dosing regimen, the total score for the MADRS item "Difficulty concentrating" was 30 at baseline for all eight patients. After 2 hours, the score dropped to 11, which corresponds to an improvement of 19 points or 63%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 29 points or 97%. On the seventh day after treatment, the score dropped to 9, which corresponds to an improvement of 21 points or 70%.

[0297] In the 12 mg group, the total score for the MADRS item "difficulty concentrating" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 14 points or 88%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

[0298] Thus, scores on scale items particularly related to impaired concentration and memory were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat impaired concentration and memory in patients, particularly those suffering from psychotic disorders such as BD.

[0299] Thus, according to the present invention, treatment of a patient suffering from cognitive dysfunction reduces or eliminates the cognitive dysfunction. Treatment reduces or eliminates impairment of concentration and memory.

[0300] Reduction or elimination of cognitive dysfunction can be reflected in improvements in scores for the BDRS items impaired concentration and memory at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0301] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the BDRS items concentration and memory impairment) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the BDRS items concentration and memory impairment) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0302] Alternatively or additionally, reduction or elimination of cognitive dysfunction may be reflected as an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0303] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the MADRS item Difficulty Concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the MADRS item Difficulty Concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0304] If the patient suffers from cognitive dysfunction, improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0305] Improvement in cognitive dysfunction, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0306] Improvement in cognitive dysfunction (assessed by a score of at least "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0307] The improvement in cognitive dysfunction (reflected by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0308] As mentioned above, "impaired concentration and memory" is an item of BDRS. Since impaired concentration and memory also affect other aspects of BD, the inventors concluded that the observed improvement in the score of the "difficulty concentrating" item on MADRS will not only bring about a related improvement in the score of the "impaired concentration and memory" BDRS scale item, but also contribute to the overall improvement of the BDRS score.

[0309] Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or alienation, symptoms of which include anhedonia, emotional withdrawal, and affect loss. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's social / emotional withdrawal or alienation.

[0310] Anhedonia (the inability to experience pleasure) has been recognized as a cardinal symptom in bipolar disorder.

[0311] Scale items that are particularly relevant to social / emotional withdrawal or alienation are “loss of feeling,” “emotional withdrawal,” and “emotional blunting.” The first item is taken from the MADRS, while the second two items are recorded in the BPRS.

[0312] The MADRS item "Anosthesia" represents the subjective experience of reduced interest in one's surroundings or in activities that normally bring pleasure. A reduced ability to respond to situations or people with appropriate emotion.

[0313] A score of 0 indicates normal interest in one's surroundings and other people, and a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 is considered a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects the experience of emotional paralysis, the inability to feel anger, grief, or pleasure, and a complete or even painful loss of affection for friends and family.

[0314] The BPRS item emotional withdrawal relates to the patient's deficits in his or her ability to connect emotionally in the interview situation. Possible scores are:

[0315] 1- No emotional withdrawal.

[0316] 2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond, occasional absent-mindedness, or an unnatural smile, but mostly engaging in spontaneous conversation with the interviewer.

[0317] 3 - Mild. Lack of emotional engagement, as evidenced by apparent failure to respond, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

[0318] 4 - Moderate. Emotional communication is rare in the interview, as the interviewee does not respond in detail, does not make eye contact, does not seem to care whether the interviewer is listening, or may be preoccupied with the psychiatric material.

[0319] 5 - Moderately severe. Same as 4, but no emotional communication was shown during most of the interview.

[0320] 6 - Severe. Actively avoids emotional engagement. Frequently unresponsive or yes / no answers (not just due to persecutory delusions). Responds with only minimal emotion.

[0321] 7 - Extreme. Consistently avoids emotional engagement. No response or yes / no answers (not just due to persecutory delusions). May walk away during the interview or simply not respond at all.

[0322] The BPRS item Affective Blunting is associated with a limited range of emotional expression in the face, voice, and gestures, as well as a marked apathy or coldness even when discussing painful topics. Possible scores are:

[0323] 1- No emotional blunting.

[0324] 2 - Very Mild. Slightly muffled or reserved emotional range, but showing appropriate facial expressions and voice intonation, within normal range.

[0325] 3 - Mild. Overall, emotional range is reduced, muted, or reserved, without many spontaneous and appropriate emotional responses. Tone is slightly monotonous.

[0326] 4 - Moderate. The range of emotions is markedly reduced, and except in rare cases, the patient will not show emotion, smile, or respond to distressing topics. There is a marked decrease in the tone of voice or spontaneous movements. Displays of emotion or gestures are usually followed by a return to apathy.

[0327] 5 - Moderate to severe. The range of emotions is very limited, the patient does not show emotion, smile, or respond to painful topics, and the facial expression does not change often except for minimal, few gestures. The tone of voice is monotonous much of the time.

[0328] 6 - Severe. Very little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression does not change. Voice intonation is monotonous most of the time.

[0329] 7 - Extreme. There is little emotional range or expression, and the movements are stiff. The tone of voice is always monotonous.

[0330] In the study group that received the individualized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to an improvement of 24 points or 67%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 34 points or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 30 points or 83%.

[0331] The total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

[0332] The total score for the BPRS item "blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

[0333] In the 12 mg group, the total score for the MADRS item "loss of sensation" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%.

[0334] In the 12 mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 2 points or 15%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 7 points or 54%.

[0335] In the 12 mg group, the total score for the BPRS item "blunting" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 3 points or 27%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 5 points or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 6 points or 55%.

[0336] Thus, the scores of the scale items particularly related to social / emotional withdrawal or alienation, namely the MADRS item "loss of sensation", the BPRS item "emotional withdrawal" and the BPRS item "blunted affect" were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat social / emotional withdrawal or alienation in patients, especially patients suffering from psychosis (such as BD), i.e., to combat "reduced social participation", "anhedonia" and / or "affective apathy".

[0337] Thus, according to the present invention, treatment of a patient suffering from social / emotional withdrawal or alienation reduces or eliminates social / emotional withdrawal or alienation. The treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

[0338] Reduction or elimination of social / emotional withdrawal or alienation is reflected in at least an improvement in the score of the BDRS items anhedonia, emotional withdrawal, and / or apathy at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0339] The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional coldness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional coldness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0340] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0341] The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the MADRS item sensory loss) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the MADRS item sensory loss) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or alienation is reflected in at least an improvement in the score of the BPRS item Emotional Withdrawal at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0343] The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item emotional withdrawal) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item emotional withdrawal) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or alienation is reflected in at least an improvement in the score of the BPRS item blunted affect at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0345] The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item Bluntedness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected by an improvement in the score of the BPRS item Bluntedness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0346] If the patient suffers from social / emotional withdrawal or alienation, improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0347] Improvement in social / emotional withdrawal or detachment, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] Improvement in social / emotional withdrawal or detachment (assessed by a score of at least "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0349] The improvement in social / emotional withdrawal or alienation (reflected by a decrease in the CGI-S or a score of at least “much improved” in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0350] As mentioned above, "reduced social participation", "anhedonia" and "affective blunting" are all items of BDRS. Since social / emotional withdrawal or alienation also affects other aspects of BD, the inventors concluded that the observed improvements in the score of the "loss of sensation" item on MADRS and the scores of "emotional withdrawal" and "affective blunting" on BPRS will not only bring about relevant improvements in the scores of the "reduced social participation", "anhedonia" and / or "affective blunting" BDRS scale items, but also promote the overall improvement of the BDRS score.

[0351] Another aspect of bipolar disorder (particularly bipolar disorder type II) that can be treated by administering 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to BD patients to reduce or eliminate the patient's suicidal ideation.

[0352] In the clinical studies involving 5-MeO-DMT administration mentioned above, the MADRS item “suicidal thoughts” was assessed, among others.

[0353] "Suicidal ideation" represents a feeling that life is not worth living, a desire to die naturally, thoughts of suicide, and / or preparations for suicide. A suicide attempt itself should not influence the assessment of this MADRS item.

[0354] A score of 0 means the patient enjoys life. If the patient is tired of life and / or has only brief suicidal thoughts, the score is 2. A score of 4 means the patient feels that death would be better, suicidal thoughts are common and suicide is considered a possible solution, but the patient has no specific plan or intention. If the patient has a clear suicide plan and / or is actively preparing for it, the score is 6.

[0355] This MADRS scale item is particularly relevant to suicidal ideation.

[0356] In the study group that received the individualized dosing regimen, the total score for the MADRS item "suicidal thoughts" for all eight patients was 11 at baseline. After 2 hours, the score dropped to 3, which corresponds to an improvement of 8 points or 73%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 10 points or 91%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 8 points or 73%.

[0357] In the 12 mg group, the total score for the MADRS item "suicidal thoughts" was 8 at baseline for all 4 patients. After 2 hours, the score dropped to 3, which corresponds to an improvement of 5 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 3 points or 38%. On the seventh day after treatment, the score dropped to 7, which corresponds to an improvement of 1 point or 13%.

[0358] Thus, the score of the scale item "suicidal thoughts", which is particularly relevant to suicidal ideation, was significantly improved, at least in the patients on the individualized dosing regimen. The inventors conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients, particularly those suffering from psychotic disorders such as BD.

[0359] Thus, according to the present invention, treatment of a patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

[0360] Reduction or elimination of suicidal ideation can be reflected as an improvement in the score of the BDRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0361] The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the BDRS item suicidal ideation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the BDRS item suicidal ideation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0362] Alternatively or additionally, reduction or elimination of suicidal ideation may be reflected as an improvement in the score of the MADRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0363] The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the MADRS item suicidal ideation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation (reflected by an improvement in the score of the MADRS item suicidal ideation) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0364] If the patient suffers from suicidal ideation, improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0365] Improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] Improvement in suicidal ideation (as assessed by a score of at least "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0367] The improvement in suicidal ideation (assessed by a decrease in the CGI-S score or a score of at least "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0368] As mentioned above, suicidal ideation is an item of the BDRS. Since suicidal ideation also affects other aspects of BD, the inventors concluded that the observed improvement in the score of the "suicidal ideation" item on the MADRS will not only bring about an associated improvement in the score of the "suicidal ideation" BDRS scale item, but also contribute to an overall improvement in the BDRS score.

[0369] Another aspect of bipolar disorder (particularly bipolar II disorder) that may be treated by administration of 5-MeO-DMT is episodes with mixed features, in which patients may experience the above-mentioned depressive symptoms, but may also exhibit symptoms such as psychotic symptoms, irritability, lability, increased motor drive, increased verbalization, and agitation. MADRS items associated with these additional symptoms include inner tension (58% improvement observed after 2 hours; 77% improvement on day 1; 54% improvement on day 7 in the IDR cohort; 85% improvement observed after 2 hours; 77% improvement on day 1; 62% improvement on day 7 in the 12 mg cohort) (which may be related to irritability and agitation), pessimistic thoughts (reflected in feelings of guilt or annihilation delusions) (which may be related to psychotic symptoms (reflected in pessimism, guilt, or delusions)), and difficulty concentrating (which may be related to increased verbalization (reflected in distractibility, among other factors)). In addition, the BPRS item guilt may be related to psychotic symptoms, while the BPRS item “tension” (31% improvement after 3 hours and on day 1, and 38% improvement on day 7 observed in the IDR cohort; 36% improvement after 3 hours, and 57% improvement on days 1 and 7 observed in the 12 mg cohort) may be related to irritability and agitation.

[0370] Improvement in one or more aspects of BD will also result in overall improvement. Preferably, treatment results in remission.

[0371] Relief of depressive symptoms can be reflected by a MADRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] Relief of depressive symptoms can be reflected by a BDRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0373] Further, alternatively or additionally, relief from depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurring no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] The present invention particularly provides for the treatment of depression in BD patients without inducing hypomania or mania. Preferably, the treatment of the present invention reduces or eliminates the risk of a patient developing a hypomanic or manic episode.

[0375] The risk of treatment-emergent mania or hypomania (TEM) is an important contributing factor to clinical trial design and a significant limiting factor in the treatment of bipolar disorder.

[0376] The inventors conclude that treatment with 5-MeO-DMT in accordance with the present invention reduces and / or eliminates the risk of TEM due to several factors related to the compound itself and the manner in which it is administered.

[0377] Psychoactive substances reportedly associated with TEM are DMT, ayahuasca (containing DMT and MAO inhibitors), psilocybin, and LSD. These substances induce a psychoactive state that develops over the course of several minutes, lasts for several hours, and is related to the user's level of involvement in the state itself, during which there is ample opportunity for positive and / or negative affective experiences. This extended window of experience provides more opportunity for manic triggering events to occur.

[0378] In contrast, 5-MeO-DMT has a rapid onset (only seconds) and usually lasts less than 30 minutes. This provides a brief but intense experience, giving patients a limited window to experience it.

[0379] Furthermore, the nature of the psychoactive phase of 5-MeO-DMT is qualitatively different from that reported for the aforementioned psychoactive substances, as it results in a disintegration or loss of self, without the feelings of cognitive engagement that accompany the experience previously associated with the use of TEM-related substances. The inventors conclude that a deep and intense 5-MeO-DMT experience significantly reduces the risk of triggering mania or hypomania.

[0380] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an increased affinity for the 5-HT1A receptor, in which case 5-MeO-DMT acts as a potent agonist, whereas the effects of these other compounds are primarily mediated through 5-HT2A agonism. 5-HT1A agonists have been reported to reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits (Carhart-Harris and Nutt 2017). Additionally, the dopamine system has been implicated in causing mania (Chen 2010), and increases in dopamine drive have been associated with mania (Berk 2007). LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT (Ray, 2019).

[0381] Furthermore, reports of TEM associated with psychoactive substance use appear to indicate use of a wide range of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0382] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

[0383] Further, it has been reported that antidepressants induce isolated hypomanic events in patients suffering from treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of inducing hypomania.

[0384] The same clinical trial showed that sleep reduction significantly improved MADRS scores, while episodes of (hypo)mania are reportedly triggered by factors such as sleep reduction (Pancheri, 2019).

[0385] Thus, when treated according to the present invention, patients do not experience treatment-induced mania or hypomania.

[0386] The Young Mania Rating Scale (YMRS) can be used to assess the occurrence of treatment-induced mania or hypomania. Treatment-induced mania or hypomania is considered to be avoided if the patient's Young Mania Rating Scale (YMRS) total score is less than or equal to 15, preferably less than or equal to 12, assessed about 2 hours; 1 day; 7 days; 14 days and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] Mode of administration

[0388] Therapeutically effective amounts of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., administration by intravenous injection.

[0389] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration via injection, and examples of excipients and vehicles for such formulations are known in the art.

[0390] Dosage regimen

[0391] The present invention also provides dosage ranges, specific dosages and dosing regimens (administration regimens) and appropriate administration routes.

[0392] The present invention is based in part on the inventors' conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT, which drives the therapeutic benefits of 5-MeO-DMT in patients suffering from BD, particularly one or more of the aspects defined above, either causally or at least as a surrogate behavioral marker of a potential unknown therapeutic mechanism.

[0393] Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility in individual patients will result in a better therapeutic profile than previously tested psychedelics, dosing regimens, and routes of administration.

[0394] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0395] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be possible with other psychedelics due to the late onset and prolonged duration of psychedelic effects and the rapid development of tolerance (i.e., diminished or absent psychedelic effects following re-administration) that may persist for several days.

[0396] Patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly with a current major depressive episode (including treatment-resistant forms of these disorders, and including these disorders associated with suicidal ideation) as defined herein are treated by administering 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e., the patient is not receiving any other treatment for BD or symptoms associated with BD.

[0397] In a preferred embodiment, the dosage range of 5-MeO-DMT administered to patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly with a current major depressive episode (including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation) as defined herein is from about 1 mg to about 10 mg, or any range therein, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated based on the specified weight of the 5-MeO-DMT free base assuming the use of equimolar amounts. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Please note that in this specification, when a range is listed (such as "about 1 mg to about 10 mg"), the inventors consider all discrete values ​​within the range, some of which are explicitly mentioned, but not all of them - this is only for the purpose of brevity.

[0398] In preferred embodiments, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, particularly suffering from a current major depressive episode, as defined herein, including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response no later than about 2 hours after administration of the 5-MeO-DMT.

[0399] In preferred embodiments, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, and particularly suffering from a current major depressive episode, as defined herein, including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0400] In a preferred embodiment, improved methods of treating patients diagnosed with bipolar disorder, particularly bipolar disorder type II, as defined herein, particularly suffering from a current major depressive episode (including treatment-resistant forms of these disorders and including these disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprise administering more than a single dose of 5-MeO-DMT.

[0401] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0402] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0403] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0404] In embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0405] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until reaching 10 mg, or all administrations within that treatment block have been administered, whichever is earlier.

[0406] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

[0407] For embodiments in which the dose of a subsequent administration is increased, the dose of 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 dose of the previous administration. For example, if the first administration dose is 1 mg and the dose increase is 3 mg, the second administration dose is 4 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administration dose is 7 mg.

[0408] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg at the first administration, and then increased to a dose selected from about 4 mg to about 6 mg at the second administration, and to a dose selected from about 7 mg to about 9 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0409] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg at the first administration, and then increased to a dose selected from about 1.5 mg to about 2.5 mg at the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0410] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 8 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 8 mg.

[0411] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 1 mg to about 3 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration in the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0412] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 0.5 mg to about 1.5 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 1.5 mg to about 2.5 mg, and the third administration in the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0413] It will be appreciated that a pharmaceutically acceptable salt of 5-MeO-DMT is preferred for all of the above dosing regimens and that, assuming equimolar amounts are used, the appropriate weight of salt to be administered can be calculated based on the specified weight of the free base.

[0414] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0415] Patients can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0416] Whether a patient has a “peak psychedelic experience” can also be determined by achieving at least 60% of the maximum possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0417] According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 to the following three questions: 1. How intense was the experience; 2. How much loss of control was there; 3. How significant (i.e., profound and important) was the experience?

[0418] Aspects of the Invention

[0419] aspect

[0420] 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient diagnosed with bipolar disorder, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

[0421] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient is diagnosed with bipolar disorder type II.

[0422] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient is diagnosed with bipolar disorder type I.

[0423] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 3, wherein the patient suffers from a current major depressive episode.

[0424] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4, wherein the patient has a total score of Montgomery-Asberg Depression Rating Scale (MADRS) equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

[0425] 6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 4 or aspect 5, wherein the patient has a Bipolar Depression Rating Scale (BDRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

[0426] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment.

[0427] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses of treatment is drug therapy.

[0428] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of medication.

[0429] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 8.

[0430] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

[0431] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0432] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0433] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 11, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0434] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12, wherein the 5-MeO-DMT or a salt thereof is administered at a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak psychedelic experience.

[0435] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12 or 15, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for the first administration, then increased to a dose of about 4 mg to about 6 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

[0436] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 16, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0437] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 12 or 15, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for the first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

[0438] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 18, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0439] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 15 to 19, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

[0440] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 11 to 20, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Ocean-like Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

[0441] 22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 21, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

[0442] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of the preceding aspects, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

[0443] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 23, wherein the clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0444] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 24, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0445] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1 or 25, wherein the clinical response lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0446] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 26, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0447] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 28, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

[0449] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 29, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and relief of depressive symptoms is reflected in a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0450] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 30, wherein a clinical response is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

[0451] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 31, wherein relief of depressive symptoms is observed on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0452] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 32, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 33, wherein there is a clinical response on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

[0454] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 34, wherein the patient is in remission of depressive symptoms on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0455] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 35, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0456] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 36, wherein there is a clinical response on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

[0457] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 37, wherein the patient is in remission of depressive symptoms on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0458] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 38, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0459] 40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 39, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement of at least 75% in the BDRS; MADRS or HAM-D score compared to the corresponding score before treatment.

[0460] 41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 40, wherein the patient is in remission of depressive symptoms on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0461] 42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 41, wherein the patient does not experience treatment-induced mania or hypomania.

[0462] 43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 42, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0463] 44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the first day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours after the last administration.

[0464] 45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 44, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0465] 46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 45, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0466] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 46, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, when assessed on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0467] 48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 47, wherein the treatment results in improvement of at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social / emotional withdrawal or alienation.

[0468] 49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 48, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

[0469] 50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

[0470] 51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49, wherein the patient suffers from excessive sleep and the treatment reduces or eliminates the excessive sleep.

[0471] 52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 to 51, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] 53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 to 52, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0473] 54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 to 53, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] 55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 to 54, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] 56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49, wherein said reduction or elimination of sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item sleep disturbance.

[0476] 57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 56, wherein said reduction or elimination of sleep disturbances lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

[0477] 58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 56, wherein said reduction or elimination of sleep disturbances lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

[0478] 59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 56, wherein said reduction or elimination of sleep disturbances lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

[0479] 60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score of the MADRS item sleep loss on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0480] 61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49 or 60, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0481] 62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 49, 60 or 61, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0482] 63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 or 60 to 62, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is at least reflected in an improvement in the score for the MADRS item sleep loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0483] 64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 49, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the MADRS item sleep loss.

[0484] 65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 64, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

[0485] 66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 64, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

[0486] 67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 64, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

[0487] 68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 49, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] 69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 49 or 68, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] 70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 49, 68 or 69, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0490] 71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 49 or 68 to 70, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0491] 72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 48, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0492] 73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0493] 74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0494] 75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0495] 76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 48, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the first day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example about 24 hours, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0496] 77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 48 or 76, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0497] 78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 48, 76 or 77, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0498] 79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 48 or 76 to 78, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0499] 80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 49, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0500] 81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 80, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0501] 82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 80, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0502] 83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect or 80, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0503] 84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 83, wherein the patient suffers from psychomotor retardation and the treatment reduces or eliminates the psychomotor retardation.

[0504] 85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 84, wherein the treatment improves or eliminates decreased energy and activity and / or decreased motivation.

[0505] 86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84 or 85, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0506] 87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 to 86, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] 88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 to 87, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0508] 89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 to 88, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0509] 90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 to 89, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0510] 91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84 or 85, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

[0511] 92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 91, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

[0512] 93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 91, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

[0513] 94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 91, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

[0514] 95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 84, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0515] 96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84 or 95, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0516] 97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84, 95 or 96, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0517] 98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 or 95 to 97, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] 99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 or 95 to 98, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0519] 100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 84, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

[0520] 101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 100, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

[0521] 102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 100, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

[0522] 103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 100, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

[0523] 104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 84, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0524] 105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84 or 104, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] 106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 84, 104 or 105, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0526] 107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 or 104 to 106, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0527] 108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 84 or 104 to 107, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0528] 109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 83, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0529] 110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0530] 111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0531] 112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0532] 113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 112, wherein the patient suffers from negative thoughts and the treatment reduces or eliminates the negative thoughts.

[0533] 114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 113, wherein the treatment reduces or eliminates feelings of worthlessness; helplessness and hopelessness; and / or guilt.

[0534] 115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] 116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113 to 115, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in scores on the BDRS items worthlessness; helplessness and hopelessness; and / or guilt on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0536] 117. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113 to 116, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] 118. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113 to 117, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0538] 119. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113 to 118, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] 120. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

[0540] 121. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 120, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

[0541] 122. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 120, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

[0542] 123. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 120, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

[0543] 124. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] 125. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 124, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] 126. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114, 124 or 125, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] 127. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 124 to 126, wherein said reduction or elimination of negative thinking is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] 128. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 124 to 127, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the MADRS item pessimistic thoughts on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0548] 129. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

[0549] 130. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 129, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

[0550] 131. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 129, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

[0551] 132. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 129, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

[0552] 133. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0553] 134. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 133, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0554] 135. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114, 133 or 134, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0555] 136. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 133 to 135, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] 137. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 133 to 136, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] 138. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item guilt.

[0558] 139. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 138, wherein said reduction or elimination of negative thoughts persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

[0559] 140. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 138, wherein said reduction or elimination of negative thoughts persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

[0560] 141. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 138, wherein said reduction or elimination of negative thoughts persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

[0561] 142. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 113 or 114, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] 143. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 142, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0563] 144. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114, 142 or 143, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0564] 145. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 142 to 144, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0565] 146. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 113, 114 or 142 to 145, wherein the patient suffers from negative thinking and improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] 147. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 112, wherein the patient suffers from negative thinking and improvement in negative thinking occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0567] 148. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 147, wherein the improvement in negative thinking persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0568] 149. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 147, wherein the improvement in negative thinking persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0569] 150. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 147, wherein said improvement in negative thinking persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0570] 151. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 150, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.

[0571] 152. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0572] 153. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 151 or 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0573] 154. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 151 to 153, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0574] 155. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 151 to 154, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0575] 156. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 151 to 155, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0576] 157. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

[0577] 158. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 157, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

[0578] 159. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 157, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

[0579] 160. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 157, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

[0580] 161. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0581] 162. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151 or 161, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0582] 163. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 151, 161 or 162, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] 164. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 151 or 161 to 163, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] 165. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 151 or 161 to 164, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0585] 166. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151, wherein said reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item anxiety.

[0586] 167. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 166, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

[0587] 168. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 166, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

[0588] 169. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 166, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

[0589] 170. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 151, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] 171. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 151 or 170, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0591] 172. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 151, 170 or 171, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0592] 173. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 151 or 170 to 172, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0593] 174. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 151 or 170 to 173, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0594] 175. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 150, wherein the patient suffers from anxiety and improvement in anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0595] 176. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0596] 177. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0597] 178. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0598] 179. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 178, wherein the patient suffers from cognitive dysfunction and the treatment reduces or eliminates the cognitive dysfunction.

[0599] 180. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 179, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] 181. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179 or 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] 182. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 to 181, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] 183. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 to 182, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] 184. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 to 183, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] 185. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 179, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

[0605] 186. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items concentration and memory impairment.

[0606] 187. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

[0607] 188. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

[0608] 189. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0609] 190. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179 or 189, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] 191. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179, 189 or 190, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0611] 192. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 or 189 to 191, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0612] 193. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 or 189 to 192, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0613] 194. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item difficulty concentrating.

[0614] 195. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 194, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

[0615] 196. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 194, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

[0616] 197. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 194, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item Difficulty Concentrating.

[0617] 198. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] 199. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 179 or 198, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] 200. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179, 198 or 199, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0620] 201. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 or 198 to 200, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0621] 202. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 179 or 198 to 201, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] 203. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 178, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0623] 204. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 203, wherein the improvement in cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0624] 205. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 203, wherein the improvement in cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0625] 206. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 203, wherein the improvement in cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0626] 207. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 206, wherein the patient suffers from social / emotional withdrawal or alienation, and the treatment reduces or eliminates the social / emotional withdrawal or alienation.

[0627] 208. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 207, wherein the treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

[0628] 209. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] 210. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207 to 209, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or apathy at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0630] 211. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207 to 210, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0631] 212. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207 to 211, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0632] 213. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207 to 212, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] 214. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional apathy.

[0634] 215. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy.

[0635] 216. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy.

[0636] 217. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional apathy.

[0637] 218. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0638] 219. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 218, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0639] 220. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208, 218 or 219, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0640] 221. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 218 to 220, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0641] 222. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 218 to 221, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score for the MADRS item sensory loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] 223. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item sensory loss.

[0643] 224. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

[0644] 225. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

[0645] 226. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

[0646] 227. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] 228. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 227, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0648] 229. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208, 227 or 228, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0649] 230. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 227 to 229, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0650] 231. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 227 to 230, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0651] 232. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item emotional withdrawal.

[0652] 233. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 232, wherein said reduction or elimination of social / emotional withdrawal or alienation lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

[0653] 234. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 232, wherein said reduction or elimination of social / emotional withdrawal or alienation lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

[0654] 235. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 232, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

[0655] 236. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0656] 237. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 236, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunted affect at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0657] 238. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208, 236 or 237, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0658] 239. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 236 to 238, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] 240. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 236 to 239, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] 241. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item blunted affect.

[0661] 242. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

[0662] 243. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

[0663] 244. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

[0664] 245. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 207 or 208, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] 246. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 245, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0666] 247. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208, 245 or 246, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0667] 248. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 245 to 247, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0668] 249. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 207, 208 or 245 to 248, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] 250. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 206, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0670] 251. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 250, wherein the improvement in social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0671] 252. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0672] 253. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 251, wherein the improvement in social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0673] 254. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 253, wherein the treatment reduces or eliminates suicidal ideation.

[0674] 255. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 254, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] 256. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 254 or 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0676] 257. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 to 256, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0677] 258. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 to 257, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0678] 259. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 to 258, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0679] 260. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 254, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item suicidal ideation.

[0680] 261. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 260, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

[0681] 262. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 260, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

[0682] 263. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 260, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

[0683] 264. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 254, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item Suicidal Thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0684] 265. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 254 or 264, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] 266. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254, 264 or 265, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0686] 267. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 or 264 to 266, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0687] 268. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 or 264 to 267, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0688] 269. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 254, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item suicidal ideation.

[0689] 270. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 269, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

[0690] 271. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 269, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

[0691] 272. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 269, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

[0692] 273. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 254, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0693] 274. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 254 or 273, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] 275. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 254, 273 or 274, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] 276. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 or 273 to 275, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] 277. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 254 or 273 to 276, wherein the patient suffers from suicidal ideation and improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0697] 278. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 253, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0698] 279. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 278, wherein the improvement in suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0699] 280. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 278, wherein the improvement in suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0700] 281. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 278, wherein the improvement in suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

[0701] 282. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 281, wherein the treatment reduces or eliminates at least one of psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

[0702] Example

[0703] The following examples are set forth to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit the invention described in the claims that follow in any manner.

[0704] Example 1-5 - MeO-DMT Aerosol Generation and Administration

[0705] Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask so that a 200 μl solution volume contains the target dose of 5-MeO-DMT free base to be administered to the volunteer or patient via inhalation. A typical target dose is 1 mg to 25 mg 5-MeO-DMT. For example, for a target dose of 18 mg 5-MeO-DMT, dissolve 90 mg of 5-MeO-DMT in 100% ethanol in a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0706] Step 2: 200 μl of the solution was transferred into a dosing capsule (Storz & Bickel, Germany) containing a drip pad and then the lid of the dosing capsule was closed.

[0707] Step 3: The dosing capsules filled with the 5-MeO-DMT ethanol solution were transferred to the filling chamber of the first Volcano Medic vaporizer, which was preheated and set to 55°C. The gas flow of the vaporizer was then turned on for 60 seconds at a preset rate of approximately 12 l / min. The heated air would flow through the dosing capsules, allowing the ethanol to evaporate, while the target dose of 5-MeO-DMT remained in the capsules as a thin layer covering the stainless steel mesh. The accurate preparation of the dosing capsules was confirmed by demonstrating that the final weight gain of the capsules was approximately equal to the target dose of 5-MeO-DMT compared to the empty capsule weight.

[0708] Step 4: The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second VolcanoMedic vaporizer, which has been preheated and set to 210°C with the airflow turned on for at least 5 minutes and then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately turned on at a preset flow rate of approximately 12 l / min for 15 seconds and then turned off. This will allow the entire dose of 5-MeO-DMT to be aerosolized and distributed in the approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to approximately its initial weight.

[0709] Step 5: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After the mouthpiece is connected to the balloon, the aerosol is ready to be immediately administered to the volunteer or patient.

[0710] Step 6: To prepare for administration, ask the patient to first take 1-2 deep breaths, exhale completely, and end the process with a deep exhalation. Then, hold the mouthpiece firmly against the lips, inhale the entire volume of the balloon in one breath, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0711] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850A1, the contents of which are incorporated herein by reference.

[0712] Example 2 - Preparation of High Purity 5-MeO-DMT

[0713] 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40 ° C and then cooled to room temperature within 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed, so the batch temperature was reduced to 7 to 12 ° C within 30 minutes. Crystallization occurred after stirring at 7 to 12 ° C for 10 minutes. It was then stirred at 7 to 12 ° C for 1 hour, and the batch was subsequently filtered. After washing with MTBE (1 mL, 0.5 volumes) at 7 to 12 ° C, the batch was dried under vacuum for 3.5 hours to obtain 1.02 g of light orange solid (50% recovery). As described in WO 2020 / 169850 A1, the purity of the separated solid was analyzed by HPLC. The purity is 99.74% area.

[0714] The analytical results further indicated that the level of individual impurities was less than 0.10% area. Solvent analysis of the sample indicated MTBE level was 17 ppm.

[0715] Example 3-5-Preparation of MeO-DMT Hydrobromide

[0716] 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0717] 5-MeO-DMT free base was combined with isopropyl acetate (10 vol) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The mixture was maintained at this temperature and equilibrated for 3 hours.

[0718] After 1 hour, a suspension was formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuo at 40°C for 18 hours.

[0719] An off-white crystalline material was obtained.

[0720] The salt has a melting point of 174°C and is characterized in that it has an X-ray diffraction pattern comprising peaks at 14.5°2·±0.2°2·; 16.7°2·±0.2°2·; 17.0°2·±0.2°2·; 20.6°2·±0.2°2·; 20.7°2·±0.2°2·; 21.4°2·±0.2°2·; 24.2°2·±0.2°2·; 24.8°2·±0.2°2·; 25.3°2·±0.2°2·; 27.4°2·±0.2°2·; which is measured using Cu K· radiation.

[0721] Example 4 - Determination of Inhibition Constants of Central 5-HT1A and 5-HT2A Receptors in Postmortem Human Brain Membranes Preparations

[0722] In the present study, the affinity of three psychedelic test compounds (psilocybin dephosphate, DMT, and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue (from the hippocampus and frontal cortex, respectively) was determined using radioligand binding techniques.

[0723] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors died suddenly, had no history of coma, psychiatric or neurological disease, were under 65 years old, and had a postmortem interval of less than or equal to 72 hours.

[0724] Binding to 5-HT1A receptors in postmortem human hippocampus

[0725] The hippocampus was homogenized in ice-cold 0.25M sucrose (1:30 weight / volume) using an electric Teflon pestle (grinded 12 times at 120rpm). Myelin and cell debris were removed by centrifugation at 1,000g for 10 minutes. The supernatant was stored on ice, and the precipitate was homogenized again in 0.25M sucrose (1:15 weight / volume) and centrifuged at 750g for 10 minutes. The supernatant was merged and diluted with ice-cold membrane preparation buffer (1:100 weight / volume), using a tightly fitting glass / Teflon homogenizer (12 times, 800rpm), and centrifuged at 20,500g for 10 minutes. The precipitate was resuspended in ice-cold membrane preparation buffer, incubated at 37°C for 10 minutes, and then centrifuged at 20,500g for 10 minutes. The precipitate was resuspended and centrifuged for the last time to wash the tissue (20,500xg, 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equal to 3.125 mg tissue wet weight / ml. All centrifugations were performed at 4°C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl2, and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM Pargyline.

[0726] For saturation binding assays, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μl of 0.075–9.6 nM [ 3 H] 8-OH-DPAT and 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (non-specific binding) were incubated for 30 minutes at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0727] In the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were mixed with 50 μl of 0.6 nM [ 3 H] 8-OH-DPAT and 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (non-specific binding) or 50 μl of one of the test compounds at one of ten concentrations between 1 and 10000 nM were incubated at 25°C for 30 min.

[0728] Membrane-bound radioactivity was recovered by vacuum filtration through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. The filters were quickly washed with ice-cold wash buffer (wash settings 0,9,9) and radioactivity was determined by liquid scintillation counting (1 ml Packard MV Gold scintillation counter).

[0729] Nonlinear regression was used to calculate the compound concentration required to inhibit specific binding by 50% (IC 50 ) and the Hill slope. K was calculated using a single-site binding model that allowed for ligand depletion. i .

[0730] Binding to 5-HT2A receptors in postmortem human frontal cortex

[0731] The frontal cortex was homogenized in ice-cold 0.25M sucrose (1:30 weight / volume) using an electric Teflon pestle (12 times at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice, and the pellet was homogenized again in 0.25M sucrose (1:15 weight / volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 weight / volume), homogenized using a tightly fitting glass / Teflon homogenizer (12 times, 800 rpm), and centrifuged at 20,500 g for 10 minutes. The pellet was further centrifuged twice to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, with a tissue concentration equal to 10 mg tissue wet weight / ml. All centrifugations were performed at 4°C.

[0732] For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight / tube) were incubated with 50 μl of 0.00625–0.8 nM [ 3 H]MDL-100,907 and 50 μl of assay buffer or 50 μl of 10 μM ketanserin (non-specific binding) were incubated for 60 minutes at 25° C. Assay and wash buffers consisted of 50 mM Tris-HCl buffer pH 7.4.

[0733] In the displacement assay, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight tissue / tube) were incubated with 50 μl of 0.1 nM [3H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 60 min at 25°C.

[0734] Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

[0735] result

[0736] Confirmed 3 The dissociation constant (K) of 8-OH-DPAT for 5-HT1A receptors in the hippocampal membrane of postmortem human brain tissue from three donors d The obtained dissociation constant (K d values) were 0.51, 0.28 and 0.52 nM, respectively.

[0737] Average inhibition constants (K) of dephosphorylated psilocybin, DMT, and 5-MeO-DMTi The Hill slopes of all compounds were close to unity, indicating a single-site binding model.

[0738] Confirmed 3 Dissociation constant (K) of MDL-100,907 for 5-HT2A receptors in the frontal cortex membranes of postmortem human brain tissue from three donors d The obtained dissociation constant (K d values) were 0.11, 0.08 and 0.08 nM respectively.

[0739] Average inhibition constants (K) of dephosphorylated psilocybin, DMT, and 5-MeO-DMT i The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

[0740] The selectivity ratios of dephosphorylated psilocybin, DMT, and 5-MeO-DMT for 5-HT2A receptors over 5-HT1A receptors are 0.78, 3.1, and 68, respectively.

[0741] Example 5 - Clinical Trial in Patients Suffering from TRD

[0742] A Phase 1 / 2 clinical trial of 5-MeO-DMT administered via inhalation as described herein has been completed in patients with treatment-resistant major depressive disorder (TRD). This trial is designed in two parts. Part A is an open-label, single-arm, single-dose Phase 1 trial with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B is an open-label, single-arm Phase 2 trial with an individualized dosing regimen and a step-wise increase in the 5-MeO-DMT dose within the patient. Patients (n=8) receive at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) per day, with higher doses only being administered when the previously administered dose does not achieve a peak experience. The primary endpoint of Part A is to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in TRD patients. The primary endpoint of Part B is to evaluate the effect on depression severity, as assessed by the proportion of patients who are relieved on the seventh day after administration, with relief defined as a total MADRS score of less than or equal to 10.

[0743] In Part A, 3 of 4 patients in both groups (12 mg and 18 mg) experienced at least one ADR, all of which were mild and resolved spontaneously. No SAEs were reported.

[0744] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission on day 7 after dosing, and another patient (25%) in the 18 mg group had MADRS clinical response on day 7 after dosing. The mean MADRS change from baseline on day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0745] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0746] At day 7, seven of eight patients (87.5%) achieved MADRS remission, achieving the primary endpoint (p<0.0001). The mean MADRS change from baseline at day 7 was 24.4 (76%).

[0747] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or measures of cognitive function in Part A or Part B.

[0748] The results are summarized in the table below.

[0749]

[0750]

[0751] Table 1-A Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment 2 hours (MADRS) or 3 hours (BPRS) after administration of the last dose.

[0752] Scale items Scale Baseline IDR Day 1 Improvement on Day 1 Percent Improvement Reduced sleep MADRS 25 12 13 52.00％ Difficulty concentrating MADRS 30 1 29 96.67％ Laziness MADRS 27 5 22 81.48％ Loss of sensation MADRS 36 2 34 94.44％ Inner tension MADRS 26 6 20 76.92％ Pessimistic thoughts MADRS 28 4 24 85.71％ Suicidal thoughts MADRS 11 1 10 90.91％ Guilt BPRS 34 11 23 67.65％ nervous BPRS 16 11 5 31.25％ anxiety BPRS 37 16 21 56.76％ Emotional withdrawal BPRS 13 8 5 38.46％ Emotional blunting BPRS 15 8 7 46.67％

[0753] Table 1-B Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessment on Day 1.

[0754]

[0755]

[0756] Table 1-C Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 7.

[0757]

[0758] Table 2-A Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment 2 hours (MADRS) or 3 hours (BPRS) after dose administration.

[0759]

[0760]

[0761] Table 2-B Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 1.

[0762]

[0763] Table 2-C Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 7.

[0764] Example 6-5-Pharmacokinetic Evaluation of MeO-DMT and Toxoplasmamine

[0765] To study the pharmacokinetic properties of 5-MeO-DMT, three groups of 8 subjects were divided. A single dose of 6 mg, 12 mg or 18 mg 5-MeO-DMT was administered to the subjects via inhalation. Blood samples were obtained at 1; 2; 4; 7; 10; 15; 20; 30; 45 minutes and 1; 1.5; 2; 3; 4 hours after administration, respectively.

[0766] 5-MeO-DMT concentrations were determined using LC-MS / MS. PK parameters were generated by algebraic analysis of concentration versus time plots for each individual. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0767] The median Cmax values ​​obtained for the three groups were 11.85 ng / ml (6 mg group), 22.90 ng / ml (12 mg group), and 38.45 ng / ml (18 mg group), respectively.

[0768] Table 3 below shows the median percentage of plasma concentration relative to Cmax determined at the indicated time points.

[0769]

[0770] Pharmacokinetic measurements were also performed for a dosing regimen that relied on up-titration, and substantially similar results were obtained.

[0771] The blood concentration of the 5-MeO-DMT metabolite bufotoxin was also determined. Only in a few samples were the concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). From 15 minutes onwards, the bufotoxin concentrations were always below the LLOQ.

[0772] Essentially similar observations were made when subjects who received an up-titration regimen were included.

[0773] Example 7-5-Toxicology Testing of MeO-DMT

[0774] 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101). These conditions included treatment at concentrations up to 5000 μg / plate (the maximum concentration recommended according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

[0775] Example 8 - Clinical Trial of Administering 5-MeO-DMT to Patients with Postpartum Depression via Inhalation

[0776] This single-arm, open-label clinical trial will involve 15 adult female patients clinically diagnosed with postpartum depression (PPD).

[0777] Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

[0778] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

[0779] 1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

[0780] 2. The second dose (12 mg) will be administered only in the following cases:

[0781] a. Peak experience (total score ≥ 75) not achieved after 6 mg dose, and

[0782] b. According to the researchers, the 6 mg dose was safe and well tolerated.

[0783] c. Any psychoactive effects (PsE) from the previous dose have resolved, and

[0784] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0785] 3. Similarly, the third dose (18 mg) will only be administered if:

[0786] a. Peak experience not achieved after 12 mg dose (total score ≥ 75), and

[0787] b. According to the researchers, the 12 mg dose was safe and well tolerated, and

[0788] c. Any PsE from the previous dose has resolved, and

[0789] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0790] Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

[0791] All patients considered for participation in a clinical trial must meet the following criteria:

[0792] 1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

[0793] 2. Body mass index (BMI) at screening is between 18.5 and 35 kg / m 2 is within the range of (including the end value).

[0794] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

[0795] a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

[0796] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

[0797] 6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express / discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

[0798] 4. Must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods for 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day -1).

[0799] 5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

[0800] Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

[0801] 1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

[0802] 2. One or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

[0803] 3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

[0804] 4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

[0805] 5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

[0806] 6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

[0807] 7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

[0808] 8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0809] 9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

[0810] 10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

[0811] 11. Patient has a positive pregnancy test at Screening or the day before testing (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

[0812] 12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0813] The primary objective of the trial was to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female patients with PPD.

[0814] Secondary objectives were to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

[0815] The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening could be performed as needed) following single-day administration of a single individualized IDR (6 mg, 12 mg, and 18 mg 5-MeO-DMT) to adult female PPD patients as measured by LC / MS / MS.

[0816] The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

[0817] Secondary endpoints included evaluation of the antidepressant effects of 5-MeO-DMT by:

[0818] The antidepressant effects of 5-MeO-DMT were evaluated by:

[0819] ○ Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

[0820] ○ Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

[0821] ○ Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0822] ○ Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0823] Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

[0824] Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

[0825] 5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

[0826] To evaluate the safety and tolerability of 5-MeO-DMT by:

[0827] ○ Report treatment-emergent adverse events (TEAEs);

[0828] ○ Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak flow spirometry;

[0829] ○ Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA / S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

[0830] ○ Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0831] ○ Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0832] ○ Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0833] ○ Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0834] Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

[0835] ○ PsE assessment using the Peak Experience (PE) scale to assess the achievement of PE (PE scale total score ≥ 75);

[0836] ○ Challenging Experience Questionnaire (CEQ);

[0837] ○Mystical Experience Questionnaire (MEQ-30);

[0838] Duration of PsE was defined as the time from the time of study drug administration to the time when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose;

[0839] Currently, one patient diagnosed with postpartum depression by a psychiatrist has been recruited to p...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient diagnosed with bipolar disorder, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is diagnosed with bipolar disorder type II.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is diagnosed with bipolar disorder type I.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 3, wherein the patient suffers from a current major depressive episode.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 4, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 4 or claim 5, wherein the patient has a Bipolar Depression Rating Scale (BDRS) total score equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 6, wherein the patient has not achieved adequate improvement after at least two adequate courses of treatment.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses is drug therapy.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 6, wherein the patient has not adequately improved after at least two adequate courses of medication.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 9, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 8.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 11, wherein a dose of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 11, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 11, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12 or 15, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 16, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12 or 15, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 18, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 15 to 19, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 11 to 20, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 21, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 22, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 23, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 24, wherein a clinical response is observed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1 or 25, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 26, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 27, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 28, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 50% improvement in BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 29, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 30, wherein a clinical response is observed on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 31, wherein relief of depressive symptoms is observed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score equal to or less than 10; a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 32, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 33, wherein there is a clinical response at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 34, wherein the patient has a reduction in depressive symptoms as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less, or a HAM-D score of 7 or less on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 35, wherein the clinical response as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 36, wherein there is a clinical response at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 37, wherein on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the patient has a reduction in depressive symptoms as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less, or a HAM-D score of 7 or less.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 38, wherein the clinical response, as reflected by at least a 50% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 39, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by at least a 75% improvement in the BDRS, MADRS or HAM-D score compared to the corresponding score before treatment.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 40, wherein the patient has a reduction in depressive symptoms on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a BDRS score of 10 or less; a MADRS score of 10 or less, or a HAM-D score of 7 or less.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 41, wherein the patient does not experience treatment-induced mania or hypomania.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 42, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score of less than or equal to 15, preferably less than or equal to 12, as assessed on day 1, e.g. about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 44, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 45, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 46, wherein the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 15, preferably less than or equal to 12, as assessed on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 47, wherein the treatment results in improvement in at least one of sleep disturbance, psychomotor retardation, negative thinking, anxiety, cognitive dysfunction, and social / emotional withdrawal or alienation.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 48, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 49, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 49, wherein the patient suffers from excessive sleepiness and the treatment reduces or eliminates the excessive sleepiness.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 to 51, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 to 52, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 to 53, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 to 54, wherein said reduction or elimination of sleep disturbances is reflected at least in an improvement in the score of the BDRS item sleep disturbances on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 49, wherein said reduction or elimination of sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbance.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 56, wherein said reduction or elimination of sleep disturbances is sustained until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 56, wherein said reduction or elimination of sleep disturbances is sustained until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 56, wherein said reduction or elimination of sleep disturbances is sustained until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item sleep disturbances.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 49, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score of the MADRS item sleep loss on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 49 or 60, wherein said sleep disturbance is sleep loss and said reduction or elimination of sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49, 60 or 61, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score of the MADRS item sleep loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 or 60 to 62, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance is reflected at least in an improvement in the score for the MADRS item sleep loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 49, wherein the sleep disturbance is sleep loss and the reduction or elimination of the sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the MADRS item sleep loss.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 64, wherein said sleep disturbance is sleep loss and said reduction or elimination of sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 64, wherein said sleep disturbance is sleep loss and said reduction or elimination of sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 64, wherein said sleep disturbance is sleep loss and said reduction or elimination of sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sleep loss.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 49, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 49 or 68, wherein the patient suffers from sleep disturbance and improvement in sleep disturbance is reflected in a decrease in Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49, 68 or 69, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 49 or 68 to 70, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 48, wherein the patient suffers from a sleep disorder and improvement in the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 72, wherein the improvement in sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 72, wherein the improvement in sleep disturbance persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 72, wherein the improvement in sleep disturbance persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 48, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example about 24 hours, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 48 or 76, wherein the patient suffers from sleep disturbances and the reduction or elimination of sleep disturbances is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 48, 76 or 77, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 48 or 76 to 78, wherein the patient suffers from a sleep disorder and the reduction or elimination of the sleep disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period is from the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 49, wherein the patient suffers from a sleep disorder and said reduction or elimination of the sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 80, wherein the patient suffers from a sleep disorder and said reduction or elimination of the sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 80, wherein the patient suffers from a sleep disorder and said reduction or elimination of the sleep disorder persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 80, wherein the patient suffers from a sleep disorder and said reduction or elimination of the sleep disorder persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, wherein the recall period spans from the time point at which the acute psychedelic experience resolved after the last administration to the assessment time point.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 83, wherein the patient suffers from psychomotor retardation and the treatment reduces or eliminates the psychomotor retardation.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 84, wherein said treatment improves or eliminates decreased energy and activity and / or decreased motivation.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 85, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 to 86, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 to 87, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 to 88, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 to 89, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 85, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 91, wherein said reduction or elimination of psychomotor retardation is sustained until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 91, wherein said reduction or elimination of psychomotor retardation is sustained until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 91, wherein said reduction or elimination of psychomotor retardation is sustained until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items decreased energy and activity and / or decreased motivation.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 84, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 95, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazyness on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84, 95 or 96, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 95 to 97, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 95 to 98, wherein said reduction or elimination of psychomotor retardation is reflected at least in an improvement in the score of the MADRS item lazy on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 84, wherein said reduction or elimination of psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazy.

101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 100, wherein said reduction or elimination of psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 100, wherein said reduction or elimination of psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 100, wherein said reduction or elimination of psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item lazyness.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 84, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 84 or 104, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84, 104 or 105, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 104 to 106, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 or 104 to 107, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 83, wherein the patient suffers from psychomotor retardation and improvement in psychomotor retardation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 109, wherein the improvement in psychomotor retardation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 109, wherein the improvement in psychomotor retardation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 109, wherein the improvement in psychomotor retardation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 112, wherein the patient suffers from negative thoughts and the treatment reduces or eliminates the negative thoughts.

114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 113, wherein said treatment reduces or eliminates feelings of worthlessness; feelings of helplessness and hopelessness; and / or feelings of guilt.

115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 to 115, wherein said reduction or elimination of negative thoughts is reflected in an improvement in scores on the BDRS items worthlessness; helplessness and hopelessness; and / or guilt at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

117. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 to 116, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

118. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 to 117, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

119. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 to 118, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

120. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

121. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 120, wherein said reduction or elimination of negative thoughts, as reflected by improvements in scores on the BDRS items worthlessness; helplessness and hopelessness; and / or guilt, persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

122. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 120, wherein said reduction or elimination of negative thoughts, as reflected by improvements in scores on the BDRS items worthlessness; helplessness and hopelessness; and / or guilt, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

123. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 120, wherein said reduction or elimination of negative thoughts is sustained until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items worthlessness; helplessness and hopelessness; and / or guilt.

124. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the score of the MADRS item pessimistic thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

125. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 124, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the score of the MADRS item pessimistic thoughts on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

126. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114, 124 or 125, wherein said reduction or elimination of negative thinking is reflected in an improvement in the score of the MADRS item pessimistic thoughts at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

127. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 124 to 126, wherein said reduction or elimination of negative thinking is reflected in an improvement in the score of the MADRS item pessimistic thoughts at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

128. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 124 to 127, wherein said reduction or elimination of negative thinking is reflected in an improvement in the score of the MADRS item pessimistic thoughts at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

129. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein said reduction or elimination of negative thinking occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item pessimistic thoughts.

130. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 129, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the MADRS item pessimistic thoughts, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

131. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 129, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the MADRS item pessimistic thoughts, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

132. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 129, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the MADRS item pessimistic thoughts, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

133. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 113 or 114, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

134. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 133, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the score of the BPRS item guilt at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

135. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114, 133 or 134, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the score of the BPRS item guilt at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

136. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 133 to 135, wherein said reduction or elimination of negative thoughts is reflected in an improvement in the score of the BPRS item guilt at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

137. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 133 to 136, wherein said reduction or elimination of negative thoughts is reflected at least in an improvement in the score of the BPRS item guilt on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

138. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein said reduction or elimination of negative thoughts occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item guilt.

139. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 138, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the BPRS item guilt, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

140. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 138, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the BPRS item guilt, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

141. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 138, wherein said reduction or elimination of negative thoughts, as reflected by an improvement in the score of the BPRS item guilt, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

142. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113 or 114, wherein the patient suffers from negative thinking and an improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

143. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 142, wherein the patient suffers from negative thinking and an improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

144. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114, 142 or 143, wherein the patient suffers from negative thinking and an improvement in negative thinking is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

145. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 142 to 144, wherein the patient suffers from negative thinking and an improvement in negative thinking is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

146. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 113, 114 or 142 to 145, wherein the patient suffers from negative thinking and an improvement in negative thinking is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

147. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 112, wherein the patient suffers from negative thinking and an improvement in negative thinking occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

148. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 147, wherein the improvement in negative thinking persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

149. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 147, wherein the improvement in negative thinking persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

150. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 147, wherein the improvement in negative thinking persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

151. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 150, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.

152. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 151, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

153. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 152, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

154. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 to 153, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

155. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 to 154, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

156. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 to 155, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BDRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

157. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 151, wherein the reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the BDRS item anxiety.

158. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 157, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

159. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 157, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

160. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 157, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item Anxiety.

161. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 151, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

162. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 161, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

163. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151, 161 or 162, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

164. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 161 to 163, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

165. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 161 to 164, wherein said reduction or elimination of anxiety is reflected at least in an improvement in the score of the BPRS item Anxiety on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

166. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 151, wherein the reduction or elimination of anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination is reflected in an improvement in the score of the BPRS item anxiety.

167. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 166, wherein said reduction or elimination of anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

168. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 166, wherein said reduction or elimination of anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item anxiety.

169. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 166, wherein said reduction or elimination of anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item Anxiety.

170. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 151, wherein the patient suffers from anxiety and improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

171. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 170, wherein the patient suffers from anxiety and the improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

172. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151, 170 or 171, wherein the patient suffers from anxiety and improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

173. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 170 to 172, wherein the patient suffers from anxiety and improvement in anxiety is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

174. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 151 or 170 to 173, wherein the patient suffers from anxiety and improvement in anxiety is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

175. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 150, wherein the patient suffers from anxiety and an improvement in anxiety occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

176. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 175, wherein the improvement in anxiety persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

177. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 175, wherein the improvement in anxiety persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

178. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 175, wherein the improvement in anxiety persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

179. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 178, wherein the patient suffers from cognitive dysfunction and the treatment reduces or eliminates the cognitive dysfunction.

180. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179, wherein said reduction or elimination of cognitive dysfunction is reflected in an improvement in the score of the BDRS items concentration and memory impairment about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

181. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 180, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

182. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 to 181, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

183. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 to 182, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

184. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 to 183, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score of the BDRS items concentration and memory impairment on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

185. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

186. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

187. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

188. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 185, wherein said reduction or elimination of cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the scores of the BDRS items concentration and memory impairment.

189. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

190. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 189, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item difficulty concentrating on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

191. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179, 189 or 190, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

192. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 189 to 191, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

193. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 189 to 192, wherein said reduction or elimination of cognitive dysfunction is reflected at least in an improvement in the score for the MADRS item Difficulty Concentrating on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

194. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179, wherein said reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item difficulty concentrating.

195. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 194, wherein said reduction or elimination of cognitive dysfunction, as reflected by an improvement in the score of the MADRS item Difficulty Concentrating, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

196. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 194, wherein said reduction or elimination of cognitive dysfunction, as reflected by an improvement in the score of the MADRS item Difficulty Concentrating, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

197. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 194, wherein said reduction or elimination of cognitive dysfunction, as reflected by an improvement in the score for the MADRS item Difficulty Concentrating, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

198. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

199. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 179 or 198, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

200. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179, 198 or 199, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

201. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 198 to 200, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

202. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 179 or 198 to 201, wherein the patient suffers from cognitive dysfunction and improvement in cognitive dysfunction is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

203. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 178, wherein the patient suffers from cognitive dysfunction and an improvement in cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

204. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 203, wherein the improvement in cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

205. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 203, wherein the improvement in cognitive dysfunction persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

206. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 203, wherein the improvement in cognitive dysfunction persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

207. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 206, wherein the patient suffers from social / emotional withdrawal or alienation, and the treatment reduces or eliminates the social / emotional withdrawal or alienation.

208. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207, wherein the treatment reduces or eliminates at least one of anhedonia, emotional withdrawal, and emotional apathy.

209. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

210. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207 to 209, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

211. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207 to 210, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional apathy at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

212. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207 to 211, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional apathy on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

213. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207 to 212, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

214. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or emotional apathy.

215. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy.

216. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy.

217. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 214, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS items anhedonia, emotional withdrawal and / or affective apathy.

218. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

219. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 218, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

220. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, 218 or 219, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

221. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, or 218 to 220, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

222. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, or 218 to 221, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the MADRS item sensory loss on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

223. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item sensory loss.

224. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

225. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

226. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 223, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item sensory loss.

227. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

228. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 227, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

229. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, 227 or 228, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

230. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 227 to 229, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

231. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, or 227 to 230, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Emotional Withdrawal on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

232. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item emotional withdrawal.

233. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 232, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

234. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 232, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

235. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 232, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item emotional withdrawal.

236. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

237. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 236, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item blunted affect at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

238. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, 236 or 237, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

239. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 236 to 238, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

240. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 236 to 239, wherein said reduction or elimination of social / emotional withdrawal or alienation is reflected at least in an improvement in the score of the BPRS item Bluntedness on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

241. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BPRS item blunted affect.

242. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item Bluntedness.

243. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item blunted affect.

244. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 241, wherein said reduction or elimination of social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BPRS item Blunted Emotion.

245. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 207 or 208, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

246. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 245, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

247. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, 245 or 246, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score at 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

248. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208 or 245 to 247, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

249. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 207, 208, or 245 to 248, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

250. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 206, wherein the patient suffers from social / emotional withdrawal or alienation and improvement in social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

251. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 250, wherein the improvement in social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement is reflected at least in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

252. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 251, wherein the improvement in social / emotional withdrawal or alienation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the improvement being reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

253. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 251, wherein the improvement in social / emotional withdrawal or alienation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement is reflected at least in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

254. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 253, wherein said treatment reduces or eliminates suicidal ideation.

255. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

256. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254 or 255, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

257. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 to 256, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

258. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 to 257, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

259. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 to 258, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the BDRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

260. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the BDRS item suicidal ideation.

261. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 260, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

262. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 260, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

263. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 260, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the BDRS item suicidal ideation.

264. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item Suicidal Thoughts about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

265. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 or 264, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

266. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254, 264 or 265, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

267. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 or 264 to 266, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

268. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 or 264 to 267, wherein said reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

269. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254, wherein said reduction or elimination of suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and said reduction or elimination is reflected in an improvement in the score of the MADRS item suicidal ideation.

270. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 269, wherein said reduction or elimination of suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

271. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 269, wherein said reduction or elimination of suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

272. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 269, wherein said reduction or elimination of suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said reduction or elimination being reflected in an improvement in the score of the MADRS item suicidal ideation.

273. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

274. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 254 or 273, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

275. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254, 273 or 274, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

276. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 or 273 to 275, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

277. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 254 or 273 to 276, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

278. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 253, wherein the patient suffers from suicidal ideation and an improvement in suicidal ideation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

279. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 278, wherein the improvement in suicidal ideation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

280. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 278, wherein the improvement in suicidal ideation persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

281. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 278, wherein the improvement in suicidal ideation persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

282. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 281, wherein the treatment reduces or eliminates at least one of psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

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