5-MeO-DMT for the treatment of bipolar disorder

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used in the treatment of patients diagnosed with bipolar disorder, and the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

Description

[Technical field]

[0001] The present invention is directed to an improved method for treating bipolar disorder (BD), comprising administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, which not only improves depressed mood, but also improves other characteristic aspects of BD, such as sleep disturbances, psychomotor developmental retardation (reduced energy and activity, and reduced motivation), negative thoughts (feelings of worthlessness, helplessness, and hopelessness, guilt), anxiety, cognitive impairment (impaired concentration and memory), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and flat affect).

[0002] The treatment also counteracts suicidal ideation. Furthermore, the treatment improves the mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0003] Treatment methods according to the invention reduce or eliminate the risk of treatment-emergent mania or hypomania. [Background technology]

[0004] Bipolar disorder is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (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 indicative of 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, either insomnia or sleeping too much, either restlessness or slowness of movement, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, thinking about, planning, or attempting suicide.

[0006] Typically, a major depressive episode includes five or more of these symptoms. Major depressive episodes include symptoms that are severe enough to cause significant difficulty in everyday situations, such as work, school, social activities, or relationships.

[0007] During a manic or hypomanic episode, the patient acts or feels unusually active, happy or irritable, and the patient often makes impulsive decisions with little consideration for the consequences. There is usually also a decreased need for sleep.

[0008] When the elevated mood is severe or associated with psychosis it is called mania, and when it is not severe it is called hypomania. Hypomania is not accompanied by psychotic symptoms.

[0009] In bipolar disorder, periods of depression and periods of abnormally elevated mood can each last from a few days to a few weeks. Mood swing episodes may occur infrequently or multiple times a year.

[0010] Traditionally, bipolar disorder was called manic depression. However, it has long been recognized that the condition is distinct from major depressive disorder. It was not until the Diagnostic and Statistical Manual of Mental Disorders III (DSM-III; 1980) that distinct bipolar disorder (BD) with mania was first formally separated from non-bipolar major depressive disorder (MDD).

[0011] If there has been at least one manic episode with or without a depressive episode, BD is classified as bipolar I disorder. If there has been at least one hypomanic episode (but no full manic episode) and one major depressive episode, BD is classified as bipolar II disorder. If these symptoms are due to drugs or medical problems, it is not diagnosed as bipolar disorder.

[0012] While hypomania is a milder form of mania, bipolar II disorder is not a milder form of bipolar I disorder. A 13.6-year study of the natural history of bipolar II disorder found that patients exhibited symptoms in 53.9% of follow-up weeks, and depressive symptoms were present in 50.3% of 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 in patients suffering from bipolar I disorder found that patients were symptomatic for 47.3% of follow-up weeks, with depressive symptoms accounting for 31.9% of 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 symptom state in both types of bipolar disorder, but especially in bipolar II disorder. Evidence suggests that rates of suicide attempts are higher in patients suffering from bipolar II disorder (Karanti, A., Kardell, M., Joas, E., Runeson, B., Palsson, E. and Landen, M., 2019. Characteristics of bipolar I and II disorder: 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 limited success due to, for example, often limited or non-sustained therapeutic response, slow onset of response, side effects that limit long-term drug administration, and inconvenient dosing schedules that often limit patient compliance.

[0014] Evidence for and against the use of antidepressants in BD patients remains largely conflicting (Baldessarini 2020), with a recent national study finding that 54.9% of patients suffering from bipolar II disorder were treated with antidepressants (Karanti, Kardell et al. 2020). This is contrary to the fact that several reports have shown that BD patients treated with antidepressants may experience clinical deterioration, symptoms such as agitation, insomnia, anger and irritability, and an increased risk of suicidal behavior (Baldessarini 2020). Treatment-emergent mania or hypomania (TEM) is a significant risk associated with such treatment.

[0015] Numerous treatment options other than antidepressants are available for BD, but many of these are associated with adverse effects. Quetiapine, approved for the acute treatment of depressive episodes in both bipolar I and II disorders, is associated with weight gain, dry mouth, sedation, somnolence, and dizziness, leading to higher discontinuation rates due to adverse effects 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 usually titrated over a multi-day period, resulting in a delayed onset of effect. Lurasidone has been shown to be associated with higher rates 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 cause somnolence and weight gain (Tohen, Vieta et al. 2003).

[0016] The predominance of depression as a psychopathology in treated BD is associated not only with excess morbidity but also with mortality from common medical comorbidities: the risk of medical and cardiovascular disorders, including diabetes or metabolic syndrome, and the associated mortality are several-fold higher than in the general population or in patients with other psychiatric disorders.

[0017] Furthermore, the standardized mortality ratio for suicide in BD is more than 20 times higher than the rate in the general population and exceeds the rate in any other major psychiatric disorder.

[0018] The current status of treatment outcomes for BD is aptly summarized by Baldessarini et al: "All available pharmacological treatments used for bipolar depression have limited efficacy and carry the risk of metabolic or neurological adverse effects."

[0019] Therefore, novel therapeutic agents for BD represent a major unmet medical need.

[0020] Although there has been considerable interest in hallucinogens in the treatment of psychiatric disorders recently, so far they have not been used as therapeutic agents for BD, due to the general lack of relevant clinical data that would allow conclusions to be drawn about their clinical usefulness in BD, but also due to the specific concern that hallucinogens may actually exacerbate the disease, particularly by inducing mania or hypomania.

[0021] Hallucinogens, including hallucinogens, are chemical compounds, some of natural origin and some synthetic, which are defined by their ability to induce perceptual distortions (such as altered hearing and vision) as well as mood and cognitive distortions in humans after ingestion. The term hallucinogen encompasses a fairly broad group of psychoactive molecules with different mechanisms of action. It has been suggested that some psychiatric disorders are in principle suitable for treatment by psychoactive molecules such as hallucinogens.

[0022] However, no psychedelic drugs have been approved by any regulatory agency, and indeed clinical experience with such molecules remains quite limited.

[0023] One compound already being investigated in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO2020 / 169850 reports clinical trials on patients suffering from treatment-resistant depression (TRD) (i.e., a form of major depressive disorder) along with studies on healthy subjects.

[0024] Against this background, it is an object of the present invention to provide therapies, and in particular dosing regimens and routes of administration for such therapies, which are more effective than previously described therapies (i.e., a) a higher percentage of patients experiencing a clinical response, b) a higher mean clinical response, c) a faster onset of clinical response, and / or d) a more sustained clinical response).

[0025] A further object of the present invention is to provide compounds for improved psychoactive therapies and dosage regimens and routes of administration for such therapies that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and dosage regimens and routes of administration for such therapies that are more favorable than previously described therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and dosage regimens and routes of administration for such therapies that are associated with a higher rate of patient compliance (higher rate of treatment initiation) than previously described therapies. Yet a further object of the present invention is to identify specific disease states and specific subgroups of disease states that would benefit from such improved psychoactive therapies. Summary of the Invention

[0026] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof for use in the treatment of a patient diagnosed with bipolar disorder.

[0027] The patient may be diagnosed with bipolar II disorder or bipolar I disorder. Typically, the patient being treated will be experiencing a major depressive episode. The patient may have been previously treated, but unsuccessfully.

[0028] In the context of the present invention, 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous administration.

[0029] The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered at a dose or dosing regimen that causes the patient to experience a hallucinogenic high. Dosages of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharma- ceutically acceptable salt thereof may be administered.

[0030] Success of treatment may be assessed by a variety of scales, including but not limited to the Bipolar Depression Rating Scale (BDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Severity Scale (CGI-S). Treatment produces a variety of therapeutic effects.

[0031] For example, a clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, generally occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and is noted on day 1 (e.g., about 24 hours).

[0032] When treating a sleep disorder, a clinical response, as reflected, for example, by a reduction in CGI-S score, generally occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0033] The clinical response preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0034] Patients do not experience treatment-emergent mania or hypomania.

[0035] In particular, treatment improves at least one of sleep disorders, psychomotor developmental delay, negative thinking, anxiety, cognitive impairment, and social / emotional withdrawal or isolation.

[0036] Additionally, the treatment reduces or eliminates suicidal thoughts.

[0037] Treatment also reduces or eliminates at least one of the following symptoms: psychosis, irritability, lability, increased motor impulsivity, increased speech, and agitation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] definition When used in the context of the present invention, unless otherwise stated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that 5-MeO-DMT pharma-ceutically acceptable salts are also typically used. Such salts are particularly acid addition salts, and 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 triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated from the weight of the free base, assuming that an equimolar amount is used.

[0039] As used in the context of the present invention, the "patient" to be treated is a human subject who has been diagnosed with bipolar disorder (such as bipolar II disorder) by a licensed professional in accordance with accepted medical practice. The diagnosis can be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) published by the American Psychiatric Association. The diagnosis is made by a physician or psychologist. It is not sufficient for the human subject to consider himself or herself to be suffering from the disorder.

[0040] As used in the context of the present invention, "suicidal ideation" refers to thinking, considering, or planning about suicide. The presence of suicidal ideation in a patient will be diagnosed by a doctor or psychologist using established protocols and methods for diagnosing suicidal tendencies. Usually, it is not enough for the patient to consider themselves as suffering from suicidal ideation. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of or to have "the intention to commit suicide."

[0041] As used in the context of the present invention, unless otherwise stated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0042] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" is intended to mean an amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0043] "Clinical response" includes, but is not limited to, improvements in rating scales. Such scales evaluate various disease aspects. Scales that can be used according to the present invention include the Brief Psychotic Rating Scale (BPRS), Bipolar Depression Rating Scale (BDRS), Montgomery-Asberg Depression Rating Scale (MADRS) and the 17-item Hamilton Depression Rating Scale (HAM-D). Further relevant scales for evaluating clinical outcome include the Young Mania Rating Scale (YMRS), Clinical Diagnostic Dissociative Scale (CADSS), Brief Psychotic Rating Scale (BPRS) and Columbia Suicide Severity Rating Scale (C-SSRS).

[0044] Clinical response may also be assessed based on the Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I).

[0045] In addition to the individual items of the scales presented, subcombinations of the individual items may be used to assess specific disease aspects.

[0046] If the clinical response is evaluated at an early time point (e.g., 2 hours) after drug administration based on an endpoint that is established with a longer recall period (e.g., MADRS usually 7 days), such endpoint can be reasonably modified (e.g., the recall period of MADRS is changed to 2 hours, and the sleep items recorded at baseline before drug administration are carried forward). The same applies to the BDRS (especially the sleep disturbance items) and any other scales applied herein, unless the recall period is specifically indicated.

[0047] At early time points the considerations outlined apply, on the one hand because the influence of the patient's condition before treatment on any scores recorded after treatment to assess the clinical response should be kept as low as possible, and on the other hand because sleep items cannot be assessed 2 hours after administration of the drug.

[0048] At later time points (e.g., day 1 or later), all items on the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0049] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbance. The PSQI is a self-rating questionnaire that includes 19 questions. Respondents are asked to indicate how frequently they have experienced a given sleep difficulty over the past month or another appropriate recall window.

[0050] The 19 self-assessed questions assess various factors related to sleep quality, including estimates of sleep duration and latency, and the frequency and severity of specific sleep-related problems. These 19 items are grouped into 7 component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleep medications; and (7) daytime dysfunction.

[0051] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbance. Detailed scoring instructions for the Pittsburgh Sleep Quality Index can be found in the appendix to Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0052] The scores on the seven components are then summed to yield one global score ranging from 0 to 21 points, with "0" indicating no difficulties and "21" indicating severe difficulties in all areas. A global score cutoff of 5 distinguishes poor from good sleepers. A global score >5 indicates that the patient has severe difficulties in at least two areas or moderate difficulties in more than three areas.

[0053] When the PSQI is used to assess treatment outcome, success of treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0054] The Verbal Recognition Memory (VRM) test assesses verbal memory and novel learning. It measures the ability to encode and later retrieve verbal information. The task presents 18 words on a screen and participants are asked to recall them during a subsequent free recall phase. A recognition test then takes place in which participants are shown 36 words (including target words and distractors) and are asked to answer "yes" or "no" as to whether they have seen the words before. This is followed by another recognition test after a 20-minute delay period, this time with a new set of distractor words. The administration time is approximately 6 minutes (including immediate and delayed recall).

[0055] The Rapid Visual Information 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 digits 2-9 appear on the screen in a pseudorandom order at a rate of 100 digits per minute. 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 digit of the target sequence is seen. The 9-digit target sequence appears at a rate of 100 digits per minute. The task takes approximately 7 minutes to complete.

[0056] The spatial working memory (SWM) task requires the storage and manipulation of visuospatial information. This self-sequencing test provides an index of strategy as well as an index of working memory errors. In the test, several colored squares (boxes) are presented on the screen and a selection strategy is required to fill in the empty columns. The test takes approximately 4 minutes to complete. SWM performance measures include errors and strategies. The SWM task used in this study is a computerized Corsi Block version.

[0057] The Digit Symbol Substitution Test (DSST) is the original paper-and-pencil version of the task adapted 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 horizontal row of squares at the top of the screen in which nine digits are randomly associated with specific symbols. Identical symbols are presented in a fixed order at the bottom of the screen, as are individual answer buttons in a horizontal row. The randomization method is chosen so that symbols never appear in the same ordinal position in both rows. The coding scheme and answer buttons remain visible while the patient is continuously presented with single digits in the center of the screen. The task is to match each digit with a symbol in the coding list and click the corresponding answer button. The number of digits correctly coded within 3 minutes is the performance measure.

[0058] Treatment outcome is assessed using one or more indexes or scales at one or more time points following completion of the course of treatment.

[0059] The evaluation may be performed after the acute hallucinatory experience has subsided. A suitable time point for early evaluation is about 2-3 hours after the last dose. The evaluation may be performed, for example, about 2 hours or about 3 hours after the last dose.

[0060] If more than one index or scale is assessed, they cannot be assessed simultaneously. Thus, one index or scale can be assessed about 2 hours after the last administration of 5-MeO-DMT, and another index or scale can be assessed, for example, about 3 hours after the last administration of 5-MeO-DMT. As used herein, assessments at both time points, or generally within a time frame of about 2-3 hours, are considered to be equally reflective of early treatment outcome.

[0061] Evaluation on day 1 or evaluation on day 1 means evaluation on the day after dosing. Evaluation will be performed no earlier than 12 hours after the last dose, and in any case no earlier than one night after the last dose and no later than 36 hours after the last dose. Evaluation may be performed after about 24 hours.

[0062] Assessment on day 7 or assessment at day 7 refers to assessment on the 7th day after dosing (the day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0063] As used in the context of the present invention, unless otherwise stated, the term "administration" (or "application") shall mean the introduction, which may be a predetermined amount, of an active compound or pharmaceutical ingredient to a patient via any route. The active compound is administered by intravenous administration, by intramuscular administration or by subcutaneous administration.

[0064] As used in the context of the present invention, unless otherwise stated, the terms "dose" and "dosage" and "dosage amount" are intended to mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosing regimen") is intended to mean a defined sequence of one or more individual administrations.

[0065] Bipolar disorder Bipolar disorder is characterized by a variety of symptoms and has a variety of manifestations.

[0066] The primary psychopathology is depression, and patients presenting with a depressive episode may initially be diagnosed with major depressive disorder (MDD). However, BD has several features that define it as distinct from MDD, even during the depressive episode.

[0067] Of particular interest here are symptoms that are more strongly associated with BD than with other psychiatric disorders, since they are the criteria by which treatment of patients is evaluated. Although many symptoms are sometimes said to cross-over into multiple disorders, much research has been done to identify some symptoms that are more prominent in BD patients: sleep disturbances, psychomotor developmental delays (reduced energy and activity, and decreased motivation), negative thinking (feeling worthless, helplessness and hopelessness, guilt), anxiety, cognitive dysfunction (concentration and memory problems), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and flat affect). Characteristic symptoms further include suicidal ideation. Even more characteristic symptoms include mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0068] Clinical assessment tools that take these symptoms into account, such as the Bipolar Depression Rating Scale (BDRS), have been developed and validated for use in BD.

[0069] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items assess the severity of depressive and / or mixed symptoms that the patient has experienced in the current and past few days. If there is a symptom discrepancy between the current and past few days, the rating should reflect the current symptoms. The scale contains 20 questions, with a maximum possible score of 60. Higher scores indicate higher severity.

[0070] Questions address: depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; flat affect; feelings of worthlessness; helplessness and hopelessness; suicidal thoughts; guilt; psychotic symptoms; irritability; lability; increased motor impulsivity; increased speech; and agitation.

[0071] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3.

[0072] Depressed mood is scored as 0 when there is no self-reported and / or observed depression as manifested by feelings of gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) when there is brief or transient depression or mild depressed mood; 2 (moderate) when depressed mood is evident but not consistently present and other emotions are present or when depression is of moderate intensity; and 3 (severe) when depressed mood is of marked intensity, pervasive, or persistent.

[0073] Sleep disorders (sleep dysregulation) are assessed based on the change in total sleep over a 24-hour cycle and are assessed independent of exogenous influences. Sleep disorders can take the form of either insomnia (a decrease in total sleep time) or hypersomnia (an increase in total sleep time, including daytime sleep).

[0074] Insomnia is assessed using a score of 0 (no reduction in total sleep time), 1 (mild, reduction of up to 2 hours), 2 (moderate, reduction of 2-4 hours), or 3 (severe, reduction of more than 4 hours).

[0075] Hypersomnia, on the other hand, is scored as 0 (no increase in total sleep time, including daytime sleep), 1 (mild, less than 2 hours or normal amount of sleep but without restorative effect), 2 (moderate, 2-4 hours), or 3 (severe, more than 4 hours).

[0076] Appetite disorders are assessed based on changes in appetite and food intake and are assessed independent of exogenous influences Appetite disorders can take the form of either decreased appetite or increased appetite.

[0077] Loss of appetite is assessed using a score of 0 (no change in appetite or food intake), 1 (mild, no change in food intake but the patient reports having to force themselves to eat or that food has lost its taste), 2 (moderate, some reduction in food intake), or 3 (marked reduction in food intake, little or no food eaten).

[0078] Increased appetite, on the other hand, is assessed as a score of 0 (no change in appetite or food intake), a score of 1 (mild, no change in food intake but increased hunger), a score of 2 (moderate, some increase in food intake, e.g., eating provides relief), or a score of 3 (marked increase in food intake or food cravings).

[0079] Reduced social engagement is scored as 0 if no reduction in social and interpersonal engagement or interaction is subjectively reported, 1 (mild) if there is only a slight reduction in social engagement and no impairment in social and interpersonal functioning, 2 (moderate) if there is a clear reduction in social engagement with some functional sequelae (e.g., avoidance of some social engagement or conversation), and 3 (severe) if there is a marked reduction in social interaction or avoidance of almost all forms of social contact (e.g., refusing to answer the phone or meet with friends or family).

[0080] Decreased energy and activity can be scored as 0 if there is no decline in energy, vitality, or goal-directed behavior, 1 (mild) if the person is able to engage in usual activities but with increased effort, 2 (moderate) if there is significant decline in energy leading to a decline in some role-specific activities, or 3 (severe) if almost all role-specific activities are listless, stagnant, or absent (e.g., spending excessive time in bed, avoiding answering the phone, deteriorating personal hygiene).

[0081] Decreased motivation was scored 0 if no subjective decline in energy, motivation, and resultant goal-directed activity was reported, scored 1 (mild) if there was only slight decline in motivation and no decline in function, scored 2 (moderate) if motivation or energy was reduced and volitional activity was markedly reduced or required considerable effort to maintain a normal level of functioning, and scored 3 (severe) if motivation or energy was reduced such that goal-directed behavior or functioning was markedly reduced.

[0082] Concentration and memory impairment is scored as 0 if no subjective impairment in attention, concentration, or memory and resultant impairment is reported; 1 (mild) if there is slight impairment in attention, concentration, or memory and no impairment; 2 (moderate) if there is significant impairment in attention, concentration, or memory and some impairment; and 3 (severe) if there is marked impairment in concentration or memory and considerable impairment (e.g., inability to read or watch television).

[0083] Anxiety is scored as follows: 0, where there is no subjectively reported worry, tension, and / or physical anxiety symptoms (e.g., tremors, palpitations, dizziness, lightheadedness, pins and needles sensation, sweating, difficulty breathing, chest palpitations, or diarrhea); 1 (mild, passing worry or tension about minor things); 2 (moderate, significant anxiety, tension, or worry, or some accompanying physical characteristics); 3 (severe, marked and ongoing anxiety, tension, or worry that interferes with usual activities, or panic attacks).

[0084] Anhedonia is scored as a score of 0 (no subjective impairment in the ability to experience pleasure in everyday activities), a score of 1 (mild, slight reduction in pleasure from usual pleasurable activities), a score of 2 (moderate, significant reduction in pleasure from usual pleasurable activities, some pleasure from isolated activities maintained), or a score of 3 (severe, complete inability to experience pleasure).

[0085] Flattening of affect is scored as 0 if there is no subjective reduction in the intensity or range of emotions or feelings, 1 (mild) if there is a slight or transient reduction in the range or intensity of emotions, 2 (moderate) if there is a significant reduction in the range or intensity of emotions with some emotions preserved (e.g., inability to cry), and 3 (severe) if there is a marked and total reduction in the range of emotions or an inability to experience normal emotions.

[0086] Feeling worthless (also called simply worthlessness) is scored as 0 (no subjective feeling or thought that one's esteem or worth has decreased), 1 (mild, slightly decreased sense of one's worth), 2 (moderate, some feelings of worthlessness and thoughts of decreased worth), or 3 (severe, marked, pervasive, or persistent feeling of worthlessness; e.g., feeling that others are better off without one, inability to recognize positive attributes).

[0087] Feelings of helplessness and hopelessness (also simply called helplessness and hopelessness) characterize a subjective feeling of pessimism or depression about the future, inability to cope, or a lack of control. If absent, the score is 0. If the feeling of not being able to cope as usual or pessimism is only present occasionally and mildly, the score is 1 (mild); if the patient often feels unable to cope or has significant feelings of helplessness or hopelessness that sometimes clear up, the score is 2 (moderate); and if the feelings of pessimism, helplessness, or hopelessness are markedly and pervasively present, the score is 3 (severe).

[0088] Suicidal ideation concerns thoughts or feelings that life is not worth living and thoughts of death or suicide, with a score of 0 if there are no such thoughts, a score of 1 (mild) if there are thoughts that life is not worth living or that life is meaningless, a score of 2 (moderate) if there are thoughts of dying or dying but no active suicidal thoughts or plans, and a score of 3 (severe) if there are suicidal thoughts or plans.

[0089] Sense of guilt (also called simply guilt) can be scored as 0 if there is no subjective sense of self-blame, failure, or regret for real or imagined past wrongdoings; 1 (mild) if there is slightly decreased self-esteem or increased self-criticism; 2 (moderate) if thoughts of failure, self-criticism, feelings of inability to cope, or rumination about past failures and the impact on others are significant and recognized as excessive; and 3 (severe) if there is marked, pervasive, or persistent guilt (e.g., a sense of deserving punishment) or a clear lack of awareness that it is excessive.

[0090] Psychotic symptoms were scored 0 if there were no overvalued thoughts, delusions, or hallucinations; 1 (mild) if there were mildly overvalued thoughts (e.g., self-criticism or pessimism with no clear effect on behavior); 2 (moderate) if there were significantly overvalued thoughts that had a clear effect on behavior (e.g., strong feelings of guilt, clear belief that others would be better off without you); and 3 (severe) if there were clear psychotic symptoms (e.g., delusions or hallucinations).

[0091] Irritability is measured by reporting uncharacteristic subjective irritability, short temper, anger, verbal or physical outbursts, with a score of 0 if none are present, 1 (mild) if there is slight subjective irritability that is not likely to be clearly demonstrated, 2 (moderate) if verbal harshness and irritability are clearly observable during interview, and 3 (severe) if physical outbursts (e.g. throwing / breaking things) or extremely abusive verbal outbursts are reported.

[0092] Lability is scored as 0 if no mood lability is observed or no mood swings are reported, 1 (mild) if a mild increase in mood lability is subjectively reported, 2 (moderate) if mood lability is clearly observable and of moderate intensity, and 3 (severe) if mood lability is prominent and dominant, with frequent or dramatic mood changes.

[0093] Increased motor impulsivity concerns subjective reports and objective evidence of increased motor impulsivity and motor activity: normal motor impulsivity is scored as 0, slight increased impulsivity not observable during interview is scored as 1 (mild), increased activity and impulsivity is evident and observable is scored as 2 (moderate), and marked or persistent increased impulsivity is scored as 3 (severe).

[0094] Increased speech refers to an observed increase in either rate or volume of speech, or an observed flight of thought. This item is scored 0 if there is no such observation, 1 (mild) if there is a slight increase in rate or volume of speech, 2 (moderate) if there is flight of thought or if the patient becomes significantly more talkative and obviously distractible or has some circumlocution, but this does not interfere with the interview, and 3 (severe) if the flight of thought interferes with the interview.

[0095] Agitation is scored as 0 if no restlessness or agitation is observed, 1 (mild) if there is slight restlessness, 2 (moderate) if there is a clear increase in the level of agitation, and 3 (severe) if the agitation is marked (e.g., constant pacing or tweaking of the hands).

[0096] Although higher scores on the BDRS scale indicate greater severity, there are no universally accepted boundaries for when a patient should be considered moderately or severely ill. The BDRS score ranges used herein to indicate the severity of depressive episodes in patients with bipolar disorder are 13-18 for "mild illness," 19-23 for "moderate illness," 24-36 for "marked illness," 37-39 for "severe illness," and 40 for "very severe illness."

[0097] A variety of other measures are also useful for assessing disease severity as well as the clinical outcome of treatment.

[0098] The CGI was developed as a brief, independent assessment of a clinician's view of a patient's overall functioning before and after treatment (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0099] The CGI-Severity (CGI-S) is based on a single question in which clinicians must answer "Considering your total clinical experience with this particular population, how mentally ill is the patient at this point?" This is rated on a 7-point scale: 1 = normal, not ill at all; 2 = borderline, mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients.

[0100] The CGI-S can be used to assess treatment success by comparing pre- and post-treatment scores.

[0101] Alternatively, treatment success can be evaluated using the CGI-Improvement (CGI-I), which is similarly brief in its format. After treatment, the clinician compares the patient's overall clinical condition with that before treatment (the so-called baseline value). Again, only one question is rated on a 7-point scale: "Compared to the patient's condition at the time of admission to the project [before the start of drug therapy], this patient's condition has improved very much since the start of treatment: 1 = very much improved; 2 = very much improved; 3 = minimally improved; 4 = no change from baseline (start of treatment); 5 = minimally worsened; 6 = very much worsened; 7 = very much worsened since the start of treatment."

[0102] 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 a patient-adapted single item based on the CGI. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0103] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, SA, & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p. 382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which would be more sensitive to changes brought about by antidepressants and other forms of treatment. A higher MADRS score indicates a more severe depression. The items considered are outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal thoughts, and each item is given a score of 0 to 6. The total score ranges from 0 to 60. The range of scores used herein 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 “marked illness,” 37–39 for “severe illness,” and 40 for “very severe illness” (Thase, 2021).

[0104] Using a structured interview guide (SIGMA) for the MADRS increases 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).

[0105] The Hamilton Depression Rating Scale (Ham-D) is a clinician-administered depression rating scale. The original version included 17 items related to depressive symptoms (HDRS 17) (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). The scale was designed to be completed after an unstructured clinical interview, but a semi-structured interview guide is now available (Williams, JB, 1988. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry 45(8):742-7). A later 21-item version includes 4 items aimed at subclassifying depression.

[0106] The Young Mania Rating Scale (YMRS; Young, RC, Biggs, JT, Ziegler, VE, & 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 frequently used rating scales for assessing manic symptoms. The scale has 11 items and is based on the patient's subjective report of their clinical state over the past 48 hours. Further information is based on clinical observations made during the course of a clinical interview. Items are selected based on public descriptions of the core symptoms of mania. The YMRS is modeled after the HAM-D, with each item being given a severity rating. Four items are graded on a scale of 0 to 8 (irritability, speech, thought content, and disruptive / aggressive behavior), and the remaining seven items are graded on a scale of 0 to 4. These four items are weighted twice as much as the other items to compensate for poor cooperation in severely ill patients. Anchor points are fully documented for each severity level. The authors encourage the use of full or half points for rating once experience is gained with the scale. The scale is generally administered by a clinician or other trained rater who specializes in manic patients.

[0107] The Brief Psychiatric Rating Scale (BPRS) aims to screen psychiatric symptoms in a structured manner. The scale is one of the most widely used scales for measuring psychiatric symptoms and was first published in 1962. Its design has been updated later. The version most commonly used today includes 18 different domains for evaluation by a physician or psychologist (Overall, JE and Gorham, DR, 1962. The brief psychiatric rating scale. Psychological Reports 10, p. 799; Overall, JE and Gorham, DR, 1988. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacology Bulletin 22, p. 97).

[0108] Eighteen items (hypochondria, anxiety, emotional withdrawal, conceptual integration disorder, guilt, tension, pedantic behavior and unnatural postures, grandiosity, depressed mood, hostility, suspiciousness, hallucinatory behavior, reduced movement, uncooperativeness, unnatural thought content, emotional blunting, excitement, and disorientation) are scored, and each item is rated on a scale of 1 to 7.

[0109] The doctor or psychologist completes two tasks during the roughly 15-minute interview with the patient: · Ask the patient a series of questions from the list. · Check to see if the patient exhibits certain behaviors.

[0110] Based on the observed responses and behaviors, the physician or psychologist completes the BPRS form by rating the severity of each domain using a scale of 1 to 7 (from a score of 1 meaning the absence of a sign or symptom to a score of 7 meaning it is present at a severe level). If a specific sign or symptom cannot be rated, a score of 0 or "no rating" is recorded.

[0111] The Clinical Diagnostic Dissociative Scale (CADSS) is assessed by the examining physician through an interview with the patient. The CADSS is a 27-item scale, with 19 items scored by the subject and 8 items scored by the observer. Scoring ranges from 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).

[0112] The CADSS is divided into three components: 1) depersonalization, 2) derealization, and 3) amnesia. These subscales are summed to produce a total dissociative score. The CADSS is specifically designed to be a standardized measure of all current dissociative symptomatology.

[0113] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a detailed questionnaire that assesses both suicidal behavior and suicidal ideation, helping to identify whether there is an immediate need for medical intervention, as well as providing data for the overall evaluation of the effectiveness of treatment regarding suicidality. The C-SSRS is supported by evidence and is part of national and international public health initiatives that involve the assessment of suicidality (Posner, K., Brown, GK, Stanley, B., Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, Melvin, GA, Greenhill, L., Shen, S., and Mann, JJ, 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), p.1266-77).

[0114] The questionnaire will be administered as an interview by a licensed psychologist or physician.

[0115] The present invention provides a method for treating patients diagnosed with bipolar disorder, as defined herein, particularly bipolar II disorder, and in particular patients diagnosed with bipolar disorder who are experiencing a major depressive episode. In particular, the method includes the treatment of the above-mentioned disease aspects, namely sleep disorders, psychomotor developmental delay (reduced energy and activity and reduced motivation), negative thoughts (feelings of worthlessness, helplessness and hopelessness, guilt), anxiety, cognitive dysfunction (concentration and memory impairment), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal and flat affect).

[0116] The treatment also counteracts suicidal ideation. Furthermore, the treatment improves the mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0117] In particular, the present invention provides a method for treating depression in BD patients without inducing hypomania or mania.

[0118] Activator The above discussion indicates that BD is characterized by several aspects, and as such, poses a significant disease burden and is amenable to appropriate treatment. Thus, not only is there a need for treatment (particularly with pharmacological intervention) to improve overall disease scores, but there is also a need for treatment to improve specific aspects of the disease.

[0119] The inventors reasoned that carefully selected hallucinogens might improve the treatment of important aspects of BD and improve the disease overall.

[0120] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also called serotonin receptors (seven families are described, 5-HT1 to 5-HT7, with several subtypes). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "hallucinogens" emphasizing their primary ability to induce qualitatively altered states of consciousness, such as euphoria, ecstasy, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or near-death experiences, while other effects, such as sedation, narcosis, or hyperstimulation, are only minimal.

[0121] Chemically, serotonergic hallucinogens are either phenylalkylamines or indolamines, the indolamine class being divided into two subsets, the ergolines and the tryptamines, the latter derived from tryptamine.

[0122] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and trace amine-associated receptors.

[0123] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations) for certain psychiatric disorders suggest that these compounds may be alternatives to currently available medications for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their use in treating patients with BD.

[0124] 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 on a patient who suffered a manic attack after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that resolved, but was followed approximately 3 weeks later by a typical manic episode of psychotic magnitude. 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 on 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 switch to mania after consumption of ayahuasca, a DMT-containing preparation, in a man with bipolar disorder.

[0125] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017) A Physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0126] The inventors have considered that, in order to avoid induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, particularly in the treatment of BD patients, the compound administered must be appropriately selected and is preferably administered in a specific dosing regimen.

[0127] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a hallucinogen of particular interest for use in the treatment of bipolar disorder and its various aspects. 5-MeO-DMT has a distinct pharmacological profile that differs from the pharmacological profiles of other hallucinogenic compounds.

[0128] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both the 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0129] The inhibition constants (K) are further detailed in the Examples section below for psilocin (the dephosphorylated form of psilocybin formed after uptake of psilocybin), DMT, and 5-MeO-DMT. i The inhibition constants (K values) for 5-HT1A receptors located in the hippocampus of postmortem human brains are 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity, whereas psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. The inhibition constants (K values) for psilocin, DMT, and 5-MeO-DMT are iThe 5-HT2A receptors located in the frontal cortex of postmortem human brains have 5 nM (37, 117, and 122 nM, respectively). Thus, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0130] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has an increased affinity for the 5-HT1A receptor and acts as a strong agonist. In the case of psilocin and DMT, there is an increased contribution of 5-HT2A binding compared to 5-MeO-DMT, with the latter showing the greatest differential affinity for 5-HT1A over 5-HT2A of the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared to 5-HT2A binding compared to the other two compounds.

[0131] It has been reported that 5-HT1A receptor agonism reduces impulsivity and aggression, while 5-HT2A receptor agonism may increase these same traits in the short term. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activation leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0132] Compared to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered to patients, preferably using the administration scheme described herein, without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder and bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or nervous system disorders treated according to the present invention do not experience treatment-emerged mania or hypomania.

[0133] Additionally, reports of treatment-emergent mania or hypomania associated with psychoactive substance use have been reported where large amounts of the respective compounds (e.g., DMT / ayahuasca, psilocybin, LSD) have been used.

[0134] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0135] Furthermore, antidepressant induction of isolated hypomanic episodes has been reported in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. “Antidepressant-induced hypomania in treatment-resistant depression.” Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0136] 5-MeO-DMT can induce peak experiences (i.e. experiences characterized by a shift in emotional perspective described as "loss of self"), which often lead to an overwhelming feeling of "oneness with the universe" more rapidly than with other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g. 5-30 minutes after intravenous injection versus several hours for oral psilocybin and oral LSD). These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile that may be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0137] In particular, the default mode network, one of several RSNs, has been implicated in numerous psychiatric disorders in which connectivity abnormalities have been identified by functional MRI. This has been shown in bipolar disorder (Chai et al. 2011, Wang et al. 2016), but is associated with numerous characteristic connectivity patterns between several additional RSNs (Rai, 2021) and / or corticolimbic connections (e.g., between the prefrontal cortex and the amygdala (de Almeida 2009)), which appear to distinguish bipolar depression from unipolar depression. Although the relationship between the DMN and other RSNs in bipolar may differ from that in unipolar, the presence of connectivity abnormalities, combined with the observed improvements in BD-related symptoms and the absence of induced manic episodes in recent clinical trials, lead us to conclude that 5-MeO-DMT is suitable for the treatment of bipolar disorder, especially when administered as described herein.

[0138] Various aspects of bipolar disorder may be improved, such as sleep disturbances, psychomotor developmental delays (reduced energy and activity and reduced motivation), negative thoughts (feelings of worthlessness, helplessness and hopelessness, guilt), anxiety, cognitive impairment (concentration and memory impairment), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal and flat affect). Further aspects of the disease that may be improved include suicidal ideation and mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation). The improvements that may be achieved are reflected by clinically relevant measures.

[0139] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered to BD patients without significant risk of inducing mania or hypomania using the administration schemes and routes of administration described herein.

[0140] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The inventors have used recombinant human 5-HT7 receptors to estimate non-specific binding, and3 H]LSD and serotonin, with a K of 2.3 nM i It was decided.

[0141] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0142] 5-HT7 receptors have a role in neurogenesis, synaptogenesis and dendritic spine formation, among others, they are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0143] 5-HT7 receptors are specifically expressed in the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and in Purkinje neurons of the cerebellum.

[0144] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disturbances in this coordination may result in disease states, especially those involving sleep disorders. In patients suffering from sleep disorders, resting-state functional connectivity analysis reveals alterations in functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0145] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of that receptor in controlling the sleep / wake cycle, and the inventors believe that this allows for the treatment of patients suffering from sleep disorders with 5-MeO-DMT acting on that receptor.

[0146] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT, along with functional connectivity "resetting" of the network and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0147] The inventor further believes that the binding of 5-MeO-DMT to the 5-HT7 and 5-HT1A receptors as two mediators of the effects exerted by 5-MeO-DMT, including the functional connectivity "resetting" of the network and neuroplasticity effects, makes it possible to achieve beneficial effects even in patients suffering from other symptoms or pathologies, such as cognitive impairment, anxiety, psychomotor developmental delay, negative thinking or social / emotional withdrawal. This is supported by the clinical results demonstrated in the studies referred to herein.

[0148] Another characteristic of 5-MeO-DMT is its short half-life.

[0149] 5-MeO-DMT is primarily inactivated via a deamination pathway mediated by monoamine oxidase A, which is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0150] The inventors have investigated the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and shortly after administration.

[0151] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid drop in plasma concentrations. Already 10 minutes after administration, the concentration falls below 10% of Cmax; after 2 hours it falls below 1% of Cmax; after 3 hours 5-MeO-DMT is no longer detectable in plasma. This applies throughout the dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated administration within a time frame of 1 to 4 hours. Titrating the dose as disclosed herein does not result in accumulation and therefore does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0152] The properties of 5-MeO-DMT make the compound particularly suitable for treating patients with BD, such as bipolar II disorder, especially those experiencing a major depressive episode.

[0153] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0154] In accordance with the present invention, isotopic variants of 5-MeO-DMT and its pharma- ceutically acceptable salts may also be used. Where reference is made to the use of 5-MeO-DMT or its pharma- ceutically acceptable salts, the use of isotopic variants is also contemplated.

[0155] These variants are in particular deuterated forms of such forms of 5-MeO-DMT and pharma- ceutically acceptable salts.

[0156] A deuterated form of 5-MeO-DMT is one that has a higher deuterium content than would be expected based on the natural abundance of this isotope.

[0157] Deuterated forms of 5-MeO-DMT are specifically forms in which deuterium has been introduced at one or more defined hydrogen positions.

[0158] 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-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0159] Further examples include the formation of 5-MeO-DMT in which deuterium is introduced at one or more hydrogen positions of the N-linked methyl group. Yet further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. Furthermore, it is noted that combinations of the above substitution patterns are also contemplated.

[0160] Methods for the preparation of these compounds are known in the art.

[0161] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharma- ceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated and non-deuterated 5-MeO-DMT may also be used.

[0162] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in molar amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0163] According to the present invention, prodrugs of 5-MeO-DMT and pharma- ceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, the reference may be substituted with a 5-MeO-DMT prodrug or a salt thereof.

[0164] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be cleaved off after administration.

[0165] 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(R3 )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 , and R 1 , R 2 , R 3 , and R 4 Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0166] A preferred example of the organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 , and R 4 is defined above.

[0167] Prodrugs, particularly those of the above structure, may also be used in the form of pharma- ceutically acceptable salts.

[0168] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitrifluoroacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0169] Methods for preparing the prodrugs discussed herein are known in the art.

[0170] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less and especially 0.5 hours or less.

[0171] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0172] patient Patients treated according to the present invention will be diagnosed with bipolar disorder by a licensed professional in accordance with accepted medical practice, for example, according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) published by the American Psychiatric Association.

[0173] In one embodiment, the patient is diagnosed with bipolar II disorder. In another embodiment, the patient is diagnosed with bipolar I disorder.

[0174] Typically, whether diagnosed with bipolar II disorder or bipolar I disorder, the patient is experiencing a major depressive episode.

[0175] The severity of the current major depressive episode may be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score of 19 or greater, such as 24 or greater, particularly 37 or greater.

[0176] Alternatively, or in addition, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as 24 or greater, particularly 37 or greater.

[0177] Further alternatively, or in addition, the patient may have a Hamilton Rating Scale for Depression (HAM-D) total score of 19, such as 24 or greater, particularly 37 or greater.

[0178] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not had adequate improvement after at least two adequate therapy courses.The patient has not had adequate improvement after at least two adequate therapy courses, and at least one of the two courses is drug therapy; for example, the patient has not had adequate improvement after at least two adequate drug therapy courses.At least two previous treatment courses are particularly administered during depressive episodes.

[0179] Patients having a major depressive episode when treated according to the present invention typically achieve a Young Mania Rating Scale (YMRS) total score of 8 or less.

[0180] Treatment of BD As indicated above, the treatment methods according to the present invention address various aspects of bipolar disorder.

[0181] These include sleep disorders, psychomotor developmental delay (reduced energy and activity and motivation), negative thoughts (feelings of worthlessness, helplessness and hopelessness, guilt), anxiety, cognitive impairment (concentration and memory problems), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal and flat affect).

[0182] The treatment also counteracts suicidal ideation. Furthermore, the treatment improves the mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0183] A method of treating a patient suffering from bipolar disorder according to the invention will typically address more than one of the above aspects, and typically result in a clinical response in some or all of the above aspects, as well as an overall improvement.

[0184] According to the present invention, the above aspects can also be treated when they occur independently of bipolar disorder (e.g., 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.

[0185] Treatment methods according to the invention reduce or eliminate (or improve or eliminate) an aspect of the disease. As used herein, this means that there is an improvement (reduction) of at least one point when the aspect is assessed on the BDRS scale, or the patient is in complete remission (elimination) after treatment (i.e., the respective aspect has a score of 0).

[0186] When the aspect is rated on the MADRS scale, there is an improvement (remission) of at least 1 point, or the patient is in complete remission (elimination) following treatment (ie, the respective aspect has a score of 0).

[0187] When the aspect is rated on the BPRS scale, there is an improvement (relief) of at least 1 point or the patient is in complete remission (elimination) following treatment (ie, each aspect has a score of 1).

[0188] Clinical response may 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 a reduction in the CGI-S score of at least one grade. Preferably, a reduction in the CGI-S score of at least two grades and / or a score of 0. Particularly preferred is a reduction in the CGI-S score of at least three grades and / or a score of 0.

[0189] To further support the clinical application of 5-MeO-DMT in patients suffering from BD, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and noted certain improvements in disease aspects also commonly seen in patients with bipolar disorder. In particular, the inventors noted improvements in various symptoms and symptom combinations that are characteristic of BD.

[0190] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD, see also the Examples section below. Although TRD is a distinct condition from BD, as detailed below, the inventors have determined that certain clinical findings from the study are relevant to the design of a therapeutic agent for BD.

[0191] In the clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are the group that received a single dose of 12 mg and the group that received an intraday individualized dosing schedule (IDR), which allowed multiple ascending doses (6 mg, 12 mg and 18 mg) during the day, driven by the intensity of the patient-reported hallucinatory experience.

[0192] The collected data included evaluation of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychotic Rating Scale (BPRS). Although the focus of the study was to demonstrate treatment efficacy through an improvement in the overall MADRS score, the inventors focused on the items that make up the various scales and noticed commonalities between some of these subscore items and the symptoms outlined above as symptoms of particular interest in BD patients. Multiple patients in the collected cohort showed significant improvement in one or more of these subscore items. This result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of BD patients, especially those BD patients who exhibit these symptoms.

[0193] The specific subscore items of each scale are identified in more detail below. Although these items do not necessarily correspond verbatim to the BD-related symptoms outlined above, the inventors recognize the commonalities that exist between these items and those symptoms and conclude that improvements shown on these items translate to improvements on related symptoms that are explicitly included in BD-specific rating scales such as the BDRS. Indeed, to the extent that the association of these symptoms with BD is supported in the literature, the inventors conclude that efficacy in treating one or more of these symptoms would significantly improve the overall outcome in BD patients treated with 5-MeO-DMT.

[0194] One aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is sleep disturbance. 5-MeO-DMT can be administered to BD patients to improve their quality of sleep.

[0195] As noted by Kaplan et al., Gottlieb et al. and others, sleep disturbances, including fluctuations in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities, have been particularly noted in patients with bipolar disorder.

[0196] Furthermore, it has been suggested that the default mode network (DMN) is associated with insomnia (De Havas et al., Nie et al.). The inventors believe that the association between the DMN and insomnia, and the effect of 5-MeO-DMT on the DMN with appropriate administration and dosing, indicate that sleep dysregulation may be treated with 5-MeO-DMT.

[0197] In the aforementioned clinical trials involving administration of 5-MeO-DMT, the "decreased sleep" item of the MADRS (reflecting insomnia) was evaluated inter alia.

[0198] The "reduced sleep" item on the MADRS refers to the experience of a decreased duration or depth of sleep compared to one's normal pattern when healthy. A score of 0 is assigned if the subject sleeps as usual. A score of 2 reflects slight difficulty in falling asleep or slightly reduced, light or intermittent sleep. A score of 4 means sleep is reduced or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0199] The aggregated MADRS "Decreased Sleep" item score across all eight patients in the study arm receiving the individualized dosing regimen had a baseline of 25. At 1 day post-treatment, the earliest time point for assessing the effect of treatment on sleep, the score had decreased to 12, corresponding to a 13-point or 52% improvement. At 7 days post-treatment, the score had decreased to 9, corresponding to a 16-point or 64% improvement.

[0200] MADRS "Decreased Sleep" item scores across all 4 patients in the 12 mg group were compiled from a baseline of 12. One day after treatment, the score decreased to 10, corresponding to a 2 point or 17% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 6 point or 50% improvement.

[0201] Thus, the score for the scale item "reduced sleep", which is particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat sleep disorders in patients, particularly those suffering from psychiatric disorders such as BD.

[0202] Thus, in accordance with the present invention, by treating a patient suffering from a sleep disorder with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, the sleep disorder is reduced or eliminated.

[0203] Reduction or elimination of sleep disturbance may be reflected by an improvement in the BDRS sleep disturbance item score on at least the 1st day (e.g., about 24 hours), 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0204] The reduction or elimination of sleep disturbance, as reflected by an improvement in the BDRS sleep disturbance item score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of sleep disturbance, as reflected by an improvement in the BDRS sleep disturbance item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0205] Where the sleep disturbance is sleep reduction, reduction or elimination of the sleep disturbance may be reflected by an improvement in the MADRS sleep reduction item score on at least the 1st (e.g., about 24 hours), 7th, 14th, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0206] The reduction or elimination of sleep disturbance, as reflected by an improvement in the MADRS sleep reduction item score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of sleep disturbance, as reflected by an improvement in the MADRS sleep reduction item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0207] If the patient is suffering from a sleep disorder, improvement in the sleep disorder is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the 1st day (e.g., about 24 hours), 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0208] Improvement in sleep disturbance, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0209] Improvement in the sleep disorder, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0210] Improvement in the sleep disorder, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0211] As indicated above, sleep disturbance is an item of the BDRS. Because sleep disturbance also affects other aspects of BD, the inventors conclude that the observed improvement in the score of the "reduced sleep" item of the MADRS will not only result in a correlated improvement in the score of the "sleep disturbance" item of the BDRS scale, but will also contribute to the overall improvement of the BDRS score.

[0212] If the patient is suffering from a sleep disorder, reduction or elimination of the sleep disorder will be reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the 1st day (e.g., about 24 hours later), 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, with the recall period spanning from the time the acute hallucinatory experience after the last administration subsided to the time of evaluation.

[0213] If the patient suffers from a sleep disorder, reduction or elimination of the sleep disorder, as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, with the recall period extending from the time the acute hallucinatory experience following the last administration subsides to the time of evaluation. Reduction or elimination of the sleep disorder, as reflected by an improvement in the PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0214] Another aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administering 5-MeO-DMT is psychomotor developmental retardation (i.e., a combination of reduced energy and activity and reduced motivation). Psychomotor developmental retardation is accompanied by a slowing of thinking and a slowing of physical movement in an individual. Psychomotor impairment can cause a visible slowing of physical and emotional responses. Psychomotor developmental retardation has been observed in patients suffering from bipolar disorder. 5-MeO-DMT can be administered to BD patients to reduce or eliminate psychomotor developmental retardation in the patient (i.e., counteracting reduced energy and activity and reduced motivation).

[0215] In the clinical trials mentioned above involving administration of 5-MeO-DMT, the "fatigue" item of the MADRS was specifically evaluated.

[0216] "Fatigue" refers to difficulty in starting or slowness in initiating and performing daily activities.

[0217] A score of 0 means that there is almost no difficulty in starting anything and no slowness. If the patient has difficulty initiating activities, a score of 2 is assigned. A score of 4 means that there is difficulty in starting simple routine activities that are done with effort, sheer fatigue, and the patient is unable to do anything without assistance, a score of 6 is assigned.

[0218] This MADRS scale item is particularly relevant to psychomotor developmental delay (i.e., reduced energy and activity and reduced motivation).

[0219] The combined MADRS "Fatigue" item score across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 27. After two hours, the score had decreased to 10, corresponding to a 17-point or 63% improvement. One day after treatment, the score had decreased to 5, corresponding to a 22-point or 81% improvement. Seven days after treatment, the score had decreased to 3, corresponding to a 24-point or 89% improvement.

[0220] The MADRS "Fatigue" item score aggregated across all four patients in the 12 mg group had a baseline of 16. After 2 hours, the score had decreased to 10, corresponding to a 6 point or 38% improvement. On the 1st day after treatment, the score had decreased to 0, corresponding to a 16 point or 100% improvement. On the 7th day after treatment, the score had decreased to 3, corresponding to a 13 point or 81% improvement.

[0221] Thus, the score for the scale item "fatigue", which is particularly relevant to psychomotor developmental retardation, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat psychomotor developmental retardation (i.e., counteract the loss of energy and activity, as well as the loss of motivation) in patients, particularly those suffering from psychiatric disorders such as BD.

[0222] Thus, in accordance with the present invention, by treating a patient suffering from psychomotor developmental retardation, the psychomotor developmental retardation is reduced or eliminated. Treatment improves or eliminates the reduced energy and activity and / or reduced motivation.

[0223] Reduction or elimination of psychomotor developmental delay may be reflected by improvement in the BDRS Decreased Energy and Activity and / or Decreased Motivation item scores about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0224] The reduction or elimination of psychomotor developmental delay, as reflected by improvement in the BDRS decreased energy and activity and / or decreased motivation item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor developmental delay, as reflected by improvement in the BDRS decreased energy and activity and / or decreased motivation item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0225] Alternatively or additionally, reduction or elimination of psychomotor developmental delay may be reflected by improvement in the MADRS Fatigue item score at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0226] The reduction or elimination of psychomotor developmental delay, as reflected by improvement in the MADRS fatigue item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor developmental delay, as reflected by improvement in the MADRS fatigue item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0227] If the patient is suffering from psychomotor developmental delay, improvement in the psychomotor developmental delay is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0228] Improvement in psychomotor developmental delay, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0229] Improvement in psychomotor developmental delay, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0230] The improvement in psychomotor developmental delay, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0231] As indicated above, "decreased energy and activity" and "decreased motivation" are items of the BDRS. Because psychomotor developmental delay also affects other aspects of BD, the inventors conclude that a noted improvement in the score of the "fatigue" item of the MADRS will not only result in a correlated improvement in the scores of the "decreased energy and activity" and / or "decreased motivation" items of the BDRS scale, but will further contribute to an overall improvement in the BDRS score.

[0232] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is negative thoughts. These negative thoughts include feelings of worthlessness, helplessness and hopelessness, and guilt. 5-MeO-DMT can be administered to BD patients to reduce or eliminate these symptoms in the patient.

[0233] Symptoms such as sadness, feelings of worthlessness, and feelings of powerlessness and hopelessness have been observed in patients with bipolar disorder, and BD patients have been reported to be more susceptible to pathological, excessive, or inappropriate feelings of guilt than MDD patients.

[0234] For the purposes of this document, these symptoms are grouped together as negative thoughts.

[0235] The MADRS scale item that is particularly relevant to this aspect of BD is "negative thinking," which refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and feelings of doom.

[0236] If there are no pessimistic thoughts, a score of 0 is assigned. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score means that there is persistent self-blame, or unquestioned but still rational thoughts of guilt or guilt, and the patient is becoming increasingly pessimistic about the future. If there are delusions of ruin, remorse, or irredeemable guilt, and irrational, unwavering self-blame, a score of 6 is assigned.

[0237] The combined MADRS "pessimistic thinking" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 28. After two hours, the score had decreased to 7, corresponding to a 21-point or 75% improvement. One day after treatment, the score had decreased to 4, corresponding to a 24-point or 86% improvement. Seven days after treatment, the score had decreased to 3, corresponding to a 25-point or 89% improvement.

[0238] MADRS "pessimistic thinking" item scores across all four patients in the 12 mg group were compiled at baseline of 16. After 2 hours, the score had decreased to 8, corresponding to an 8-point or 50% improvement. On the first day after treatment, the score had decreased to 7, corresponding to a 9-point or 56% improvement. On the seventh day after treatment, the score had decreased to 8, corresponding to an 8-point or 50% improvement.

[0239] A BPRS item of particular relevance to guilt is "Guilt." This item concerns excessive preoccupation with or regret about past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift attention to other things. 3 - Mild. Preoccupied and somewhat preoccupied with disappointing someone or failing at something. Tends to express guilt to others. 4 - Moderate. Disproportionately preoccupied with feelings of guilt, having done something wrong, or having hurt others by doing or failing to do something, but can easily shift attention to other things. 5 - Moderately severe. Feelings of guilt, preoccupation with disappointing someone or failing at something, can focus on other things but only with great effort. Not delusional. 6 - Severe. Delusional feelings of guilt or irrational self-blame that is not particularly relevant to the situation. Moderately distracted. 7 - Extremely severe. Delusional feelings of guilt or irrational self-blame that is significantly unrelated to the situation. Subject is extremely preoccupied with feelings of guilt and likely to disclose to others or act on the delusion.

[0240] The BPRS "guilt" item score was compiled across all eight patients in the study group receiving the individualized dosing plan, with a baseline of 34. After three hours, the score had decreased to 14, corresponding to a 20-point or 59% improvement. One day after treatment, the score had decreased to 11, corresponding to a 23-point or 68% improvement. Seven days after treatment, the score had decreased to 10, corresponding to a 24-point or 71% improvement.

[0241] The BPRS "guilt" item scores across all four patients in the 12 mg group were compiled from a baseline of 18. After 3 hours, the score had decreased to 9, corresponding to a 9 point or 50% improvement. On the first day after treatment, the score had decreased to 5, corresponding to a 13 point or 72% improvement. On the seventh day after treatment, the score had decreased to 5, corresponding to a 13 point or 72% improvement.

[0242] Thus, scores on the MADRS scale item "pessimistic thinking", which is particularly related to negative thinking, are significantly improved, as are scores on the BPRS item "guilt". The inventors conclude that 5-MeO-DMT can be used to treat negative thinking in patients, particularly those suffering from psychiatric disorders such as BD.

[0243] Thus, in accordance with the present invention, by treating a patient suffering from negative thoughts, the negative thoughts are reduced or eliminated. Treatment reduces or eliminates feelings of worthlessness, helplessness and hopelessness, and / or feelings of guilt.

[0244] Reduction or elimination of negative thoughts may be reflected by improvements in scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0245] The reduction or elimination of negative thinking, as reflected by an improvement in the BDRS worthlessness, helplessness and hopelessness, and / or guilt item scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of negative thinking, as reflected by an improvement in the BDRS worthlessness, helplessness and hopelessness, and / or guilt item scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0246] Alternatively or additionally, reduction or elimination of negative thinking may be reflected by an improvement in the MADRS negative thinking item score at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0247] The reduction or elimination of negative thinking, as reflected by an improvement in the MADRS negative thinking item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of negative thinking, as reflected by an improvement in the MADRS negative thinking item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0248] Alternatively or additionally, reduction or elimination of negative thoughts may be reflected by an improvement in the BPRS guilt item score at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0249] The reduction or elimination of negative thinking, as reflected by an improvement in the BPRS guilt item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of negative thinking, as reflected by an improvement in the BPRS guilt item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0250] If the patient is suffering from negative thinking, improvement in negative thinking is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0251] Improvement in negative thinking, as reflected by at least a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0252] Improvement in negative thinking, as assessed by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0253] The improvement in negative thinking, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0254] As shown above, helplessness and hopelessness, worthlessness, and guilt are items of BDRS.Since negative thinking also affects other aspects of BD, we conclude that the improvement observed in the score of "pessimistic thinking" item of MADRS and "guilt" item of BPRS will not only result in the correlated improvement in the score of "worthlessness", "helplessness and hopelessness" and / or "guilt" item of BDRS scale, but will also contribute to the overall improvement of BDRS score.For example, the "psychotic symptoms" item of BDRS includes strong guilt as a contributing factor.

[0255] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to BD patients to reduce or eliminate anxiety in the patient.

[0256] The BPRS item of particular relevance to anxiety is "Anxiety." This item concerns reported apprehension, tension, fear, panic or worry. Possible scores are: 1- No worries 2 - Very mild. Reports some discomfort due to worry that occurs more than most healthy people or occasional worry. 3 - Mild. Worries often but can easily shift attention to other things. 4 - Moderate. Worried most of the time and unable to easily attend to other things but without interfering with functioning, or with occasional autonomic anxiety but without interfering with functioning. 5 - Moderately severe. Frequent (but not daily) periods of anxiety with autonomic involvement or some areas of functioning impaired by worry or anxiety. 6 - Severe. Paraautonomic anxiety is present every day but not all day or many areas of functioning are impaired by anxiety or constant worry. 7 - Extremely severe. Paraautonomic anxiety is present throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0257] Aggregated BPRS "anxiety" item scores across all eight patients in the study group receiving the individualized dosing plan had a baseline of 37. After three hours, the score had decreased to 19, corresponding to an 18-point or 49% improvement. One day after treatment, the score had decreased to 16, corresponding to a 21-point or 57% improvement. Seven days after treatment, the score had decreased to 17, corresponding to a 20-point or 54% improvement.

[0258] The BPRS "anxiety" item score was compiled across all four patients in the 12 mg group, with a baseline of 25. After 3 hours, the score had decreased to 11, corresponding to a 14-point or 56% improvement. After 1 day of treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement. After 7 days of treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement.

[0259] The inventors conclude that 5-MeO-DMT can be used to treat anxiety in patients, particularly those suffering from a psychiatric disorder such as BD.

[0260] Thus, in accordance with the present invention, by treating a patient suffering from anxiety, the anxiety is reduced or eliminated.

[0261] Reduction or elimination of anxiety may be reflected by improvement in the BDRS anxiety item at least 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0262] The reduction or elimination of anxiety, as reflected by an improvement in the BDRS anxiety item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by an improvement in the BDRS anxiety item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0263] Alternatively or additionally, reduction or elimination of anxiety may be reflected by improvement in the BPRS anxiety item at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0264] The reduction or elimination of anxiety, as reflected by an improvement in the BPRS anxiety item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by an improvement in the BPRS anxiety item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0265] If the patient is suffering from anxiety, improvement in anxiety is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0266] Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0267] Improvement in anxiety, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0268] Improvement in anxiety, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0269] As indicated above, "anxiety" is an item on the BDRS. Because anxiety also affects other aspects of BD, the inventors conclude that an improvement observed on the "anxiety" item on the BPRS will not only result in a correlated improvement on the "anxiety" item on the BDRS scale, but will also contribute to an overall improvement in the BDRS score.

[0270] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is cognitive impairment, particularly difficulty concentrating. 5-MeO-DMT can be administered to BD patients to reduce or eliminate cognitive impairment, particularly difficulty concentrating, in the patient.

[0271] Bipolar depressed patients show impairments in the domains of memory and executive function, and there is some evidence that bipolar depressed subjects have poorer executive function compared to unipolar depressed subjects. In addition, bipolar patients have been reported as having a cognitive component to their psychomotor developmental delay.

[0272] The MADRS item that is particularly relevant to concentration and memory problems is "Difficulty concentrating."

[0273] This item indicates difficulty in organizing one's thoughts and also indicates a lack of ability to concentrate. If the patient concentrates without difficulty, the score is 0. If there is occasional difficulty in organizing thoughts, the score is 2. If there is difficulty in concentrating and sustaining thoughts, which impairs the ability to read or speak, a score of 4 is assigned. If the patient is unable to read or speak without great difficulty, the score is 6.

[0274] The combined MADRS "Difficulty concentrating" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 30. After two hours, the score had decreased to 11, corresponding to a 19-point or 63% improvement. One day after treatment, the score had decreased to 1, corresponding to a 29-point or 97% improvement. Seven days after treatment, the score had decreased to 9, corresponding to a 21-point or 70% improvement.

[0275] MADRS "Difficulty concentrating" item scores across all four patients in the 12 mg group were combined at baseline of 16. After 2 hours, the score had decreased to 7, corresponding to a 9 point or 56% improvement. On the first post-treatment day, the score had decreased to 2, corresponding to a 14 point or 88% improvement. On the seventh post-treatment day, the score had decreased to 3, corresponding to a 13 point or 81% improvement.

[0276] Thus, scores on scale items particularly relevant to concentration and memory impairment are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat concentration and memory impairment in patients, particularly those suffering from psychiatric disorders such as BD.

[0277] Thus, according to the invention, by treating a patient suffering from cognitive impairment, the cognitive impairment is reduced or eliminated. Treatment reduces or eliminates impairments in concentration and memory.

[0278] Reduction or elimination of cognitive impairment may be reflected by at least improvements in scores on the BDRS concentration and memory impairment items at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0279] The reduction or elimination of cognitive impairment as reflected by improvement in the BDRS concentration and memory impairment item scores occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of cognitive impairment as reflected by improvement in the BDRS concentration and memory impairment item scores preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0280] Alternatively or additionally, reduction or elimination of cognitive impairment may be reflected by an improvement in the MADRS Difficulty Concentrating item score at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0281] The reduction or elimination of cognitive impairment as reflected by improvement in the MADRS difficulty concentrating item score occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of cognitive impairment as reflected by improvement in the MADRS difficulty concentrating item score preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0282] If the patient is suffering from cognitive impairment, improvement in the cognitive impairment is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0283] Improvement in cognitive impairment, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0284] Improvement in cognitive impairment, as assessed by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0285] Improvement in cognitive impairment, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0286] As indicated above, "Difficulty concentrating and memory" is an item of the BDRS. Because concentration and memory problems also affect other aspects of BD, the inventors conclude that an observed improvement in the score of the "Difficulty concentrating" item of the MADRS will not only result in a correlated improvement in the score of the "Difficulty concentrating and memory" item of the BDRS scale, but will also contribute to an overall improvement in the BDRS score.

[0287] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is social / emotional withdrawal or detachment, the symptoms of which include anhedonia, emotional withdrawal and loss of affect. 5-MeO-DMT can be administered to BD patients to reduce or eliminate social / emotional withdrawal or detachment in the patient.

[0288] Anhedonia (the inability to experience pleasure) is recognised as a key symptom of bipolar disorder.

[0289] Scale items of particular relevance to social / emotional withdrawal or detachment are "unable to have emotions," "emotional withdrawal," and "blunted emotion." The first item is taken from the MADRS, the latter two appear in the BPRS.

[0290] The "inability to have emotions" item on the MADRS reflects awareness of diminished interest in one's surroundings or in normally pleasurable activities. The ability to respond emotionally to situations or people is reduced.

[0291] A score of 0 indicates normal interest in the surroundings and other people, a score of 2 indicates a reduced ability to enjoy normal concerns. A score of 4 is assigned in cases of loss of interest in the surroundings and loss of emotion toward friends and acquaintances. A score of 6 reflects an experience of emotional numbness, an inability to feel anger, deep sadness, or joy, and a complete or distressing inability to care for close relatives and friends.

[0292] The emotional withdrawal item of the BPRS concerns the patient's lack of ability to relate emotionally in the interview situation. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. A lack of emotional engagement is indicated by an occasional failure to respond, appearing distracted at times, or smiling awkwardly, but most of the time engages spontaneously with the interviewer. 3 - Mild. Lack of emotional engagement is indicated by a noticeable inability to respond, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4 - Moderate. Emotional contact is absent for the majority of the interview as the subject is aloof, unable to make eye contact, does not seem to care if the interviewer is listening, or may be preoccupied with psychotic content. 5-Moderately severe. Same as "4" except emotional contact is absent for most of the interview. 6 - Severe. Actively avoids emotional involvement. Frequently unresponsive or responds with yes / no answers (not due to paranoia alone). Responds with only minimal affect. 7- Extremely severe. Consistently avoids emotional involvement. Is unresponsive or responds with yes / no answers (not due to paranoia alone). May leave during interview or not respond at all.

[0293] The blunted affect item of the BPRS concerns a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2- Very mild. Emotional range is slightly suppressed or reserved, but displays appropriate facial expressions and vocal tone that are within normal limits. 3 - Mild. The entire emotional range is muted, suppressed or reserved, without many spontaneous and appropriate emotional responses. Vocal tone is slightly monotonous. 4-Moderate. The emotional range is significantly reduced, the patient does not affect or smile, or responds minimally to distressing topics. The tone of voice is monotonous or there is a marked reduction in spontaneous movements. Any display of emotion or gesture is usually followed by a return to flat affect. 5 - Moderately severe. Emotional range is severely reduced, the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, facial expression rarely changes, and the tone of voice is monotone much of the time. 6-Severe. Extremely limited emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression is unchanging. Vocal tone is monotone most of the time. 7 - Extremely severe. Virtually no emotional range or expressiveness, stiff movements. Monotonous tone of voice all the time.

[0294] The combined MADRS "Inability to Have Emotions" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 36. After two hours, the score had decreased to 12, corresponding to a 24-point or 67% improvement. One day after treatment, the score had decreased to 2, corresponding to a 34-point or 94% improvement. Seven days after treatment, the score had decreased to 6, corresponding to a 30-point or 83% improvement.

[0295] The BPRS "emotional withdrawal" item score was tabulated with a baseline of 13. After 3 hours, the score had decreased to 8, which corresponds to a 5 point or 38% improvement. After 1 day of treatment, the score had decreased to 8, which corresponds to a 5 point or 38% improvement. After 7 days of treatment, the score had decreased to 8, which corresponds to a 5 point or 38% improvement.

[0296] The BPRS "blunted affect" item score was tallied with a baseline of 15. After 3 hours, the score had decreased to 11, which corresponds to a 4-point or 27% improvement. One day after treatment, the score had decreased to 8, which corresponds to a 7-point or 47% improvement. Seven days after treatment, the score had decreased to 8, which corresponds to a 7-point or 47% improvement.

[0297] MADRS "Inability to Have Emotions" item scores compiled across all 4 patients in the 12 mg group had a baseline of 16. After 2 hours, the score had decreased to 9, corresponding to a 7 point or 44% improvement. On the 1st day after treatment, the score had decreased to 1, corresponding to a 15 point or 94% improvement. On the 7th day after treatment, the score had decreased to 1, corresponding to a 15 point or 94% improvement.

[0298] The BPRS "emotional withdrawal" item score for the 12 mg group was tabulated with a baseline of 13. After 3 hours, the score had decreased to 11, corresponding to a 2-point or 15% improvement. On the 1st post-treatment day, the score had decreased to 8, corresponding to a 5-point or 38% improvement. On the 7th post-treatment day, the score had decreased to 6, corresponding to a 7-point or 54% improvement.

[0299] The BPRS "blunted affect" item score for the 12 mg group was compiled with a baseline of 11. After 3 hours, the score had decreased to 8, which corresponds to a 3 point or 27% improvement. On the 1st day after treatment, the score had decreased to 6, which corresponds to a 5 point or 45% improvement. On the 7th day after treatment, the score had decreased to 5, which corresponds to a 6 point or 55% improvement.

[0300] Thus, scores on scale items particularly related to social / emotional withdrawal or detachment, i.e., MADRS item "inability to have emotions", BPRS item "emotional withdrawal" and BPRS item "blunted affect", are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat social / emotional withdrawal or detachment, i.e., to counteract "reduced social engagement", "anhedonia" and / or "flattened affect", in patients, particularly those suffering from psychiatric disorders such as BD.

[0301] Thus, in accordance with the present invention, by treating a patient suffering from social / emotional withdrawal or isolation, the social / emotional withdrawal or isolation is reduced or eliminated. Treatment reduces or eliminates at least one of anhedonia, emotional withdrawal and flat affect.

[0302] Reduction or elimination of social / emotional withdrawal or detachment is reflected by at least improvements in scores on the BDRS anhedonia, emotional withdrawal and / or flat affect items on about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0303] The reduction or elimination of social / emotional withdrawal or detachment, as reflected by improvement in the BDRS anhedonia, emotional withdrawal and / or flattened affect item scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by improvement in the BDRS anhedonia, emotional withdrawal and / or flattened affect item scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0304] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement is reflected by at least an improvement in the MADRS Unable to Have Emotions item score about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0305] The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the MADRS Unable to Feel item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the MADRS Unable to Feel item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0306] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement is reflected by at least an improvement in the BPRS emotional withdrawal item score about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0307] The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the BPRS Emotional Withdrawal item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the BPRS Emotional Withdrawal item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0308] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or isolation is reflected by at least an improvement in the BPRS Blunted Affect item score at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0309] The reduction or elimination of social / emotional withdrawal or isolation, as reflected by an improvement in the BPRS Blunted Affectiveness item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation, as reflected by an improvement in the BPRS Blunted Affectiveness item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0310] If the patient is suffering from social / emotional withdrawal or detachment, improvement in the social / emotional withdrawal or detachment is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0311] Improvement in social / emotional withdrawal or detachment, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0312] Improvement in social / emotional withdrawal or isolation, as assessed by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0313] The improvement in social / emotional withdrawal or detachment, as reflected by a decrease in the CGI-S or by a score of at least "much improved" in the CGI-I or PGI-I scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0314] As indicated above, "reduced social engagement", "anhedonia" and "flat affect" are items of the BDRS. Since social / emotional withdrawal or detachment also affects other aspects of BD, the inventors conclude that the observed improvements in the "unable to have emotions" item score of the MADRS and the "emotional withdrawal" and "blunted affect" scores of the BPRS will not only result in a correlated improvement in the "reduced social engagement", "anhedonia" and / or "flat affect" item scores of the BDRS scale, but will further contribute to an overall improvement in the BDRS score.

[0315] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to BD patients to reduce or eliminate suicidal ideation in the patient.

[0316] In the aforementioned clinical trials involving administration of 5-MeO-DMT, the "suicidal thoughts" item of the MADRS was specifically assessed.

[0317] "Suicidal thoughts" refers to feelings that there is no point in living and that one would be happy to die naturally at any time, suicidal thoughts, and / or preparations for suicide. Suicide attempts themselves should not influence the rating of this MADRS item.

[0318] A score of 0 means that the patient is enjoying life. A score of 2 is assigned if the patient is bored with life and / or has only fleeting suicidal thoughts. A score of 4 means that the patient often has suicidal thoughts, such as thinking that death would be better, and suicide is considered a possible solution, but the patient has no specific plan or intent. A score of 6 is assigned if the patient has a clear plan for suicide and / or is actively preparing.

[0319] This MADRS scale item is of particular relevance to suicidal ideation.

[0320] The combined MADRS "suicidal thoughts" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 11. After two hours, the score had decreased to 3, which corresponds to an 8-point or 73% improvement. One day after treatment, the score had decreased to 1, which corresponds to a 10-point or 91% improvement. Seven days after treatment, the score had decreased to 3, which corresponds to an 8-point or 73% improvement.

[0321] MADRS "suicidal thoughts" item scores across all four patients in the 12 mg group were compiled at baseline as 8. After 2 hours, the score had decreased to 3, corresponding to a 5 point or 63% improvement. On the 1st day after treatment, the score had decreased to 5, corresponding to a 3 point or 38% improvement. On the 7th day after treatment, the score had decreased to 7, corresponding to a 1 point or 13% improvement.

[0322] Thus, scores for the scale item "suicidal thoughts," which is particularly relevant to suicidal ideation, are significantly improved in patients, at least 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 a psychiatric disorder such as BD.

[0323] Thus, in accordance with the present invention, treating a patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

[0324] Reduction or elimination of suicidal ideation may be reflected by an improvement in the BDRS suicidal ideation item score at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0325] The reduction or elimination of suicidal ideation, as reflected by an improvement in the BDRS suicidal ideation item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by an improvement in the BDRS suicidal ideation item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0326] Alternatively or additionally, reduction or elimination of suicidal ideation may be reflected by an improvement in the MADRS Suicidal Thoughts item score at least about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0327] The reduction or elimination of suicidal ideation, as reflected by an improvement in the MADRS suicidal ideation item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by an improvement in the MADRS suicidal ideation item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0328] If the patient is suffering from suicidal ideation, improvement in suicidal ideation is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, 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 pharma- ceutically acceptable salt thereof.

[0329] Improvement in suicidal ideation, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0330] Improvement in suicidal ideation, as assessed by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0331] Improvement in suicidal ideation, as assessed by a reduction in the CGI-S score, or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0332] As indicated above, suicidal ideation is an item on the BDRS. Because suicidal ideation also affects other aspects of BD, the inventors conclude that an observed improvement in the score on the "suicidal thoughts" item on the MADRS will not only result in a correlated improvement in the score on the "suicidal ideation" item on the BDRS scale, but will also contribute to an overall improvement in the BDRS score.

[0333] A further aspect of bipolar disorder, particularly bipolar II disorder, that can be treated by administration of 5-MeO-DMT is episodes with mixed features in which patients exhibit the depressive symptoms described above, but may also exhibit symptoms such as psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation. MADRS items that relate to these additional symptoms include inner tension, which may be related to irritability and agitation (58% improvement at 2 hours, 77% improvement at day 1, and 54% improvement at day 7 observed in the IDR cohort; 85% improvement at 2 hours, 77% improvement at day 1, and 62% improvement at day 7 observed in the 12 mg cohort), pessimistic thinking (reflected in feelings of guilt or delusions of doom) that may be related to psychotic symptoms (reflected in sadness, guilt, or delusions), and difficulty concentrating, which may be related to increased speech (reflected in distractibility, among other factors). Additionally, the BPRS guilt item may be associated with psychotic symptoms, and the BPRS tension item (31% improvement at 3 hours and day 1 and 38% improvement at day 7 observed in the IDR cohort, 36% improvement at 3 hours and 57% improvement at days 1 and 7 observed in the 12 mg cohort) may be associated with irritability and agitation.

[0334] Improvement in one or more aspects of BD also leads to an overall improvement. Preferably, the treatment leads to remission.

[0335] Remission of depressive symptoms may be reflected by a MADRS score of 10 or less, achieved by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and observed on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28.

[0336] Remission of depressive symptoms may be reflected by a BDRS score of 10 or less, achieved by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and observed on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28.

[0337] Further alternatively, or in addition, remission of depressive symptoms may be reflected by a HAM-D score of 7 or less, achieved by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and observed on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28.

[0338] In particular, the present invention provides a method for treating depression in BD patients without inducing hypomania or mania, and preferably reduces or eliminates the risk of the patient developing a hypomanic or manic episode.

[0339] The risk of treatment-emergent mania or hypomania (TEM) is an important factor in clinical trial design and a significant limitation for the treatment of bipolar disorder.

[0340] The inventors conclude that treatment with 5-MeO-DMT according to 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.

[0341] Psychoactive substances reported to be associated with TEM are DMT, ayahuasca (containing DMT and MAO inhibitors), psilocybin, and LSD. These substances induce a psychoactive state that builds up over minutes and lasts for hours, including a phase during which the user becomes trapped in the state, with ample opportunity for positive and / or negative emotional experiences to occur. This delayed window of experience increases the chance of a manic event occurring.

[0342] In contrast, 5-MeO-DMT has a rapid onset of effect (within a matter of seconds) and a duration that is typically less than 30 minutes, resulting in a short-lived but intense experience that limits the patient's window of experience.

[0343] Furthermore, the nature of the psychoactive phase of 5-MeO-DMT is qualitatively different from the ego-dissolution or loss of self reported for the aforementioned psychoactive substances, and there is no sense of cognitive entrapment associated with the experience previously associated with substance use. The inventors conclude that a deep and intense 5-MeO-DMT experience significantly reduces the risk of inducing mania or hypomania.

[0344] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has increased affinity for the 5-HT1A receptor and acts as a strong agonist. In contrast, the effects of these other compounds are primarily mediated through 5-HT2A receptor agonism. It has been reported that 5-HT1A receptor agonism reduces impulsivity and aggression, while 5-HT2A receptor agonism may increase these same traits in the short term (Carhart-Harris and Nutt 2017). Furthermore, the dopamine system has been implicated in the pathogenesis of mania (Chen 2010), and increased dopamine agonism leads to mania (Berk 2007). LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT (Ray, 2019).

[0345] Furthermore, TEM reports related to psychoactive substance use seem to indicate that large amounts of the respective compounds (e.g., DMT / ayahuasca, psilocybin, LSD) were used.

[0346] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0347] Furthermore, antidepressant induction of isolated hypomanic episodes has been reported in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. “Antidepressant-induced hypomania in treatment-resistant depression.” Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0348] This same clinical trial demonstrated a significant improvement in MADRS scores in response to sleep reduction, although (hypo)manic episodes have been reported to be precipitated by sleep reduction, among other factors (Pancheri, 2019).

[0349] Therefore, when treated according to the present invention, patients do not experience treatment-emergent mania or hypomania.

[0350] The onset of treatment-emergent mania or hypomania may be assessed using the Young Mania Rating Scale (YMRS). As used herein, treatment-emergent mania or hypomania is considered to be avoided if the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed about 2 hours, on days 1, 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0351] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly or subcutaneously. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., by intravenous injection.

[0352] 5-MeO-DMT may be used as a pharma- ceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations are known in the art.

[0353] Dosage regimen The present invention also provides dose ranges, specific doses as well as administration regimens (administration schemes) and suitable routes of administration.

[0354] The present invention is based in part on the inventors' conclusion that the manifestation of a hallucinogenic climax experience in the acute phase following administration of 5-MeO-DMT causally facilitates, or at least as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from BD, in particular one or more of the aspects defined above.

[0355] Consequently, achieving a peak experience more rapidly, in a greater percentage of patients, and with better reproducibility in individual patients compared to previously tested hallucinogens, dosing regimens, and routes of administration would result in a better therapeutic profile.

[0356] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerability (i.e., attenuation of hallucinogenic effects or absence of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once a day, or daily), designed to increase the incidence of peak experiences and thereby increase therapeutic benefit. Such repeated administration within a short time also allows for intra-individual dose optimization, which reduces the risk of overdosing, which may otherwise result in less meaningful hallucinogenic experiences with physical side effects, such as serotonin syndrome, negative psychological reactions, such as flashbacks of the experience at a later time, induction of mania or hypomania, or little or no memory of the altered state (so-called "whiteout"). Furthermore, starting with a low dose usually allows the patient to get used to the hallucinogenic experience and prepare for the more intense symptoms that occur at higher doses, which will favorably affect the experience at those higher doses. Additionally, the possibility of being able to initiate treatment at lower doses will increase patient acceptance of the therapeutic approach and improve overall compliance rates at the patient population level.

[0357] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate of peak experiences and modulate the reproducibility of peak experiences, as well as to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the delayed onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration) that may last for several days.

[0358] Patients as defined herein who have been diagnosed with bipolar disorder (especially bipolar II disorder) and who are particularly experiencing a major depressive episode (including treatment-resistant forms of these disorders, and including those disorders associated with suicidal ideation) are treated by administration of 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (i.e., the patient is not receiving any other treatment for BD or symptoms associated with BD).

[0359] In a preferred embodiment, the dosage of 5-MeO-DMT administered to a patient as defined herein who has been diagnosed with bipolar disorder, particularly bipolar II disorder, and who is in the midst of experiencing a major depressive episode, including treatment-resistant forms of these disorders, and including those disorders associated with suicidal ideation, ranges from about 1 mg to about 10 mg, or any amount within that range, and is administered in the form of a formulation for administration based on a pharma- ceutically acceptable salt of 5-MeO-DMT, e.g., the hydrobromide salt, the weight of which can be calculated from the stated weight of 5-MeO-DMT free base, assuming that an equimolar amount is used. Specific effective 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. It should be noted that, when a range such as "about 1 mg to about 10 mg" is given in this specification, the inventors contemplate all individual values ​​within the range, some of which are specifically recited, but not all of which are recited merely for the sake of brevity.

[0360] In a preferred embodiment, an improved method for treating a patient as defined herein who has been diagnosed with bipolar disorder (especially bipolar II disorder) and who is particularly experiencing a major depressive episode (including treatment-resistant forms of these disorders, and including those disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises generating a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0361] In a preferred embodiment, the improved method for treating a patient as defined herein who has been diagnosed with bipolar disorder (especially bipolar II disorder) and who is particularly experiencing a major depressive episode (including treatment-resistant forms of these disorders, and including those disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT includes a persistence of clinical response that occurs up to about 6 days after the last administration of 5-MeO-DMT, preferably at least about 14 days after the last administration of 5-MeO-DMT, more preferably at least about 28 days after the last administration of 5-MeO-DMT, including by about 2 hours after administration of 5-MeO-DMT.

[0362] In a preferred embodiment, the improved method for treating a patient as defined herein who has been diagnosed with bipolar disorder (especially bipolar II disorder) and who is in particular experiencing a major depressive episode (including treatment-resistant forms of these disorders, and including those disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises administering more than one dose of 5-MeO-DMT.

[0363] In a preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2-7 doses, the interval between each dose within each treatment block being greater than or equal to about 1 hour and less than or equal to about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being greater than or equal to about 6 days.

[0364] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0365] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1-3 doses, with the interval between each dose within each treatment block being about 1-4 hours, preferably 1-2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0366] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0367] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until 10 mg is reached or until all administrations within the treatment block have been administered, whichever occurs first.

[0368] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until 10 mg is reached or until all administrations within the treatment block have been administered or until the patient experiences a hallucinogenic high experience or until the supervising physician determines that further dose escalation is inappropriate based on observed side effects, whichever occurs first.

[0369] For embodiments in which the dosage is increased for a subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage of the previous administration. For example, if the dosage of the first administration is 1 mg and the dosage increment is 3 mg, then the dosage of the second administration will be 4 mg, unless one of the stopping criteria described above has been reached. Preferably, the dosage for the third administration will be 7 mg.

[0370] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration, and about 7 mg to about 9 mg for the third administration, unless the patient has yet to experience a hallucinogenic high within that treatment block or the supervising physician has determined that further dose escalation is inappropriate based on observed side effects. Specific amounts that are effective for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0371] In additional preferred embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration, and about 2.5 mg to about 3.5 mg for the third administration, unless the patient has yet to experience a hallucinogenic high within that treatment block or the supervising physician has determined that further dose escalation is inappropriate based on observed side effects. Specific amounts that are effective for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0372] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased with each subsequent administration in that first treatment block until 10 mg is reached or until all administrations in the treatment block have been administered or until the patient experiences a hallucinogenic climax experience or until the supervising physician determines that further dose escalation is inappropriate based on observed side effects, whichever occurs first, with the highest dosage in that first treatment block being used as the dosage for administration in all subsequent treatment blocks and their subsequent treatment blocks. For example, if the highest dosage in a first treatment block was 8 mg, then the dosage for administration in all subsequent treatment blocks and their subsequent treatment blocks would be 8 mg, since the patient experienced a hallucinogenic climax experience at that dose.

[0373] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of the first treatment block, then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective 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.

[0374] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of the first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective 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.

[0375] Pharmaceutically acceptable salts of 5-MeO-DMT are also preferably used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0376] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0377] The occurrence of a "hallucinatory peak experience" in a patient can be identified via achievement of at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experiences Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0378] The occurrence of a "hallucinatory peak experience" in a patient can also be identified via the achievement of at least 60% of the maximum possible score on the Oceania Infinite (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0379] In accordance with the present invention, the occurrence of a "psychedelic peak experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) total score (also called the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control was it? 3. How profound (i.e., meaningful) was the experience?

[0380] Aspects of the invention Aspects 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof for use in the treatment of a patient diagnosed with bipolar disorder, wherein the 5-MeO-DMT is administered via an intravenous, intramuscular or subcutaneous route.

[0381] 2. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 1, wherein the patient has been diagnosed with bipolar II disorder.

[0382] 3. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 1, wherein the patient has been diagnosed with bipolar I disorder.

[0383] 4. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 3, wherein the patient is experiencing a major depressive episode.

[0384] 5. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 4, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 19 or more, such as 24 or more, in particular 37 or more.

[0385] 6. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 4 or embodiment 5, wherein the patient has a Bipolar Depression Rating Scale (BDRS) total score of 19 or more, such as 24 or more, in particular 37 or more.

[0386] 7. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 6, wherein said patient has not shown sufficient improvement after at least two adequate courses of treatment.

[0387] 8. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not shown sufficient improvement after at least two adequate courses of treatment, where at least one of the two courses was a drug therapy.

[0388] 9. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient has not shown sufficient improvement after at least two courses of appropriate drug therapy.

[0389] 10. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 9, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 8 or less.

[0390] 11. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein said 5-MeO-DMT or salt thereof is administered at a dose or dosing regimen that causes said patient to experience a hallucinogenic high experience.

[0391] 12. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use according to any one of claims 1 to 11, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma-ceutical acceptable salt is administered instead of 5-MeO-DMT.

[0392] 13. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 11, wherein a dosage of about 2 mg, or about 5 mg, or about 8 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0393] 14. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 11, wherein a dosage of about 1 mg, or about 2 mg, or about 3 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0394] 15. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 12, wherein the 5-MeO-DMT or salt thereof is administered in a first dosage for a first administration, and the 5-MeO-DMT or salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration, unless the patient experiences a hallucinogenic high experience.

[0395] 16. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 1-12 or 15, wherein the 5-MeO-DMT is administered at a dosage of about 1 mg to about 3 mg for a first administration, then increased to a dosage of about 4 mg to about 6 mg for a second administration unless the patient has yet to experience a hallucinatory climax experience, and then increased to a dosage of about 7 mg to about 9 mg for a third administration unless the patient has yet to experience a hallucinatory climax experience, or an equimolar amount of the pharma-ceutically acceptable salt is administered in place of 5-MeO-DMT.

[0396] 17. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 16, wherein the first dosage of 5-MeO-DMT is about 2 mg, the second dosage of 5-MeO-DMT is about 5 mg, and the third dosage of 5-MeO-DMT is about 8 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0397] 18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 1-12 or 15, wherein the 5-MeO-DMT is administered at a dosage of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has yet to experience a hallucinatory climax experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has yet to experience a hallucinatory climax experience, or an equimolar amount of the pharma-ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0398] 19. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 18, wherein the first dosage of 5-MeO-DMT is about 1 mg, the second dosage of 5-MeO-DMT is about 2 mg, and the third dosage of 5-MeO-DMT is about 3 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0399] 20. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 15 to 19, wherein the interval between two administrations is at least 1 hour and at most 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

[0400] 21. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 11 to 20, wherein the manifestation of a hallucinogenic peak experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Mystical Experiences Questionnaire-Revised (MEQ30), or by achieving at least 60% of the maximum possible score on the Oceania-Infinity (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 75 on the total score of the Peak Experiences Scale (PES).

[0401] 22. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 21, wherein the onset of a hallucinatory peak experience is identified by achieving a total score of at least 75 on the Peak Experience Scale (PES).

[0402] 23. 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, for use according to any of the preceding aspects, wherein said 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, is administered via intravenous injection.

[0403] 24. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 23, wherein the clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0404] 25. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 24, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, is observed 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0405] 26. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 1 or 25, wherein the clinical response as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0406] 27. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the clinical response as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0407] 28. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 27, wherein the clinical response as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0408] 29. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 28, wherein a clinical response, as reflected by an improvement of at least 50% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score prior to treatment, occurs by no later than about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0409] 30. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 29, wherein remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0410] 31. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 30, wherein a clinical response, as reflected by an improvement of at least 50% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score before treatment, is observed on the 1st day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0411] 32. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 31, wherein remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less is observed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0412] 33. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 32, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score before treatment, is sustained for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0413] 34. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 33, wherein the clinical response, as reflected by an improvement of at least 75% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score before treatment, is 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0414] 35. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 34, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less, 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0415] 36. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 35, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score prior to treatment, is sustained for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0416] 37. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 36, wherein the clinical response, as reflected by an improvement of at least 75% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score before treatment, is 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0417] 38. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 37, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less, 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0418] 39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 38, wherein the clinical response, as reflected by an improvement of at least 50% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score prior to treatment, is sustained for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0419] 40. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the clinical response, as reflected by an improvement of at least 75% in the BDRS score, the MADRS score or the HAM-D score compared to the respective score before treatment, is 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0420] 41. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 40, wherein the patient is in remission of depressive symptoms as reflected by a BDRS score of 10 or less, a MADRS score of 10 or less, or a HAM-D score of 7 or less, 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0421] 42. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 41, wherein said patient does not experience treatment-emergent mania or hypomania.

[0422] 43. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 42, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0423] 44. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 43, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0424] 45. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 44, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0425] 46. ​​5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 45, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0426] 47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 46, wherein the patient has a Young Mania Rating Scale (YMRS) total score of 15 or less, preferably 12 or less, assessed 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0427] 48. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 47, wherein said treatment improves at least one of sleep disorders, psychomotor developmental delay, negative thinking, anxiety, cognitive impairment, and social / emotional withdrawal or isolation.

[0428] 49. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 48, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

[0429] 50. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

[0430] 51. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, wherein the patient suffers from hypersomnia and the treatment reduces or eliminates the hypersomnia.

[0431] 52. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 49 to 51, wherein the reduction or elimination of said sleep disturbance is reflected by at least an improvement in the score on the BDRS sleep disturbance item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0432] 53. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 49 to 52, wherein the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the BDRS sleep disturbance item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0433] 54. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 49 to 53, wherein the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the BDRS sleep disturbance item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0434] 55. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 49 to 54, wherein the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the BDRS sleep disturbance item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0435] 56. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, wherein the reduction or elimination of the sleep disturbance, as reflected by an improvement in the score on the BDRS sleep disturbance item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0436] 57. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 56, wherein the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the BDRS sleep disturbance item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0437] 58. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 56, wherein the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the BDRS sleep disturbance item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0438] 59. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 56, wherein the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the BDRS sleep disturbance item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0439] 60. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, wherein the sleep disorder is sleep reduction and the reduction or elimination of the sleep disorder is reflected by at least an improvement in the score on the MADRS sleep reduction item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0440] 61. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49 or 60, wherein the sleep disturbance is sleep reduction and the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the MADRS sleep reduction item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0441] 62. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49, 60 or 61, wherein the sleep disturbance is sleep reduction and the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the MADRS sleep reduction item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0442] 63. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49 or 60 to 62, wherein the sleep disturbance is sleep reduction and the reduction or elimination of the sleep disturbance is reflected by at least an improvement in the score on the MADRS sleep reduction item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0443] 64. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49, wherein the sleep disturbance is sleep reduction and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the MADRS sleep reduction item occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0444] 65. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 64, wherein the sleep disturbance is sleep depletion and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the MADRS sleep depletion item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0445] 66. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 64, wherein the sleep disturbance is sleep depletion and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the MADRS sleep depletion item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0446] 67. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 64, wherein the sleep disturbance is sleep depletion and the reduction or elimination of the sleep disturbance as reflected by an improvement in the score on the MADRS sleep depletion item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0447] 68. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, wherein the patient suffers from a sleep disorder and improvement of the sleep disorder is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0448] 69. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49 or 68, wherein the patient suffers from a sleep disorder, and improvement of the sleep disorder is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0449] 70. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 49, 68 or 69, wherein the patient suffers from a sleep disorder and improvement of the sleep disorder is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0450] 71. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49 or 68 to 70, wherein the patient suffers from a sleep disorder and improvement of the sleep disorder is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0451] 72. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 48, wherein the patient suffers from a sleep disorder and an improvement in the sleep disorder, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0452] 73. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in the sleep disorder as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0453] 74. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in the sleep disorder as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0454] 75. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 72, wherein the improvement in the sleep disorder as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0455] 76. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 48, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of evaluation.

[0456] 77. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of 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 by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of evaluation.

[0457] 78. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of 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 by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience following the last administration subsided to the time of evaluation.

[0458] 79. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of 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 by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of evaluation.

[0459] 80. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 49, wherein the patient suffers from a sleep disorder, and wherein reduction or elimination of the sleep disorder, as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and wherein the recall period extends from the time the acute hallucinatory experience following the last administration subsides to the time of evaluation.

[0460] 81. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 80, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score persists until at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience following the last administration subsided until the time of evaluation.

[0461] 82. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 80, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score persists until at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience following the last administration subsided until the time of evaluation.

[0462] 83. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 80, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder as reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the recall period extends from the time the acute hallucinatory experience following the last administration subsided to the time of evaluation.

[0463] 84. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 83, wherein the patient suffers from psychomotor developmental retardation and the treatment reduces or eliminates the psychomotor developmental retardation.

[0464] 85. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, wherein said treatment ameliorates or eliminates reduced energy and activity and / or reduced motivation.

[0465] 86. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84 or 85, wherein the reduction or elimination of said psychomotor developmental delay is reflected by at least an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0466] 87. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 84 to 86, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item at the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0467] 88. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 84 to 87, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0468] 89. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 84 to 88, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0469] 90. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 84 to 89, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0470] 91. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 84 or 85, wherein the reduction or elimination of said psychomotor developmental delay as reflected by an improvement in said score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0471] 92. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 91, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0472] 93. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 91, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0473] 94. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 91, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the BDRS Decreased Energy and Activity and / or Decreased Motivation item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0474] 95. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the MADRS fatigue item score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0475] 96. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 84 or 95, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS fatigue item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0476] 97. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, 95 or 96, wherein the reduction or elimination of the psychomotor developmental delay is reflected at least by an improvement in the score on the MADRS fatigue item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0477] 98. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 84 or 95 to 97, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS fatigue item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0478] 99. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 84 or 95 to 98, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS fatigue item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0479] 100. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS Fatigue item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0480] 101. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 100, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS Fatigue item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0481] 102. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 100, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS Fatigue item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0482] 103. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 100, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS Fatigue item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0483] 104. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, wherein the patient suffers from psychomotor developmental retardation, and improvement in psychomotor developmental retardation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0484] 105. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84 or 104, wherein the patient suffers from psychomotor developmental retardation, and improvement in psychomotor developmental retardation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0485] 106. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84, 104 or 105, wherein the patient suffers from psychomotor developmental retardation, and improvement in psychomotor developmental retardation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0486] 107. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84 or 104 to 106, wherein the patient suffers from psychomotor developmental retardation, and improvement in the psychomotor developmental retardation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0487] 108. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 84 or 104 to 107, wherein the patient suffers from psychomotor developmental retardation, and improvement in psychomotor developmental retardation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0488] 109. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 83, wherein the patient suffers from psychomotor developmental delay, and an improvement in the psychomotor developmental delay, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0489] 110. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor developmental delay as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0490] 111. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor developmental delay as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0491] 112. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 109, wherein the improvement in psychomotor developmental delay as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0492] 113. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 112, wherein the patient is suffering from negative thoughts and the treatment reduces or eliminates the negative thoughts.

[0493] 114. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, wherein said treatment reduces or eliminates feelings of worthlessness, feelings of helplessness and despair, and / or feelings of guilt.

[0494] 115. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 113 or 114, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0495] 116. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 113 to 115, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0496] 117. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 113 to 116, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0497] 118. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 113 to 117, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0498] 119. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 113 to 118, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0499] 120. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113 or 114, wherein the reduction or elimination of negative thoughts, as reflected by an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0500] 121. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 120, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0501] 122. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 120, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0502] 123. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 120, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the scores on the BDRS worthlessness, helplessness and hopelessness, and / or guilt items persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0503] 124. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 113 or 114, wherein the reduction or elimination of negative thinking is reflected by at least an improvement in the score on the MADRS negative thinking item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0504] 125. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, 114 or 124, wherein the reduction or elimination of negative thinking is reflected by at least an improvement in the score on the MADRS negative thinking item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0505] 126. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 113, 114, 124 or 125, wherein the reduction or elimination of negative thinking is reflected by at least an improvement in the score on the MADRS negative thinking item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0506] 127. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 113, 114 or 124 to 126, wherein the reduction or elimination of negative thinking is reflected by at least an improvement in the score on the MADRS negative thinking item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0507] 128. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 113, 114 or 124 to 127, wherein the reduction or elimination of negative thinking is reflected by at least an improvement in the score on the MADRS negative thinking item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0508] 129. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113 or 114, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the score on the MADRS negative thinking item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0509] 130. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 129, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the score on the MADRS negative thinking item, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0510] 131. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 129, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the score on the MADRS negative thinking item, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0511] 132. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 129, wherein the reduction or elimination of negative thinking, as reflected by an improvement in the score on the MADRS negative thinking item, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0512] 133. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113 or 114, wherein the reduction or elimination of said negative thoughts is reflected by at least an improvement in the score on the BPRS guilt item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0513] 134. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, 114 or 133, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the score on the BPRS guilt item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0514] 135. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, 114, 133 or 134, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the score on the BPRS guilt item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0515] 136. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 113, 114 or 133 to 135, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the score on the BPRS guilt item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0516] 137. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 113, 114 or 133 to 136, wherein the reduction or elimination of negative thoughts is reflected by at least an improvement in the score on the BPRS guilt item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0517] 138. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113 or 114, wherein the reduction or elimination of negative thoughts, as reflected by an improvement in the score on the BPRS guilt item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0518] 139. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score on the BPRS guilt item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0519] 140. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score on the BPRS guilt item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0520] 141. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 138, wherein the reduction or elimination of negative thoughts as reflected by an improvement in the score on the BPRS guilt item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0521] 142. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113 or 114, wherein the patient is suffering from negative thoughts, and improvement in negative thoughts 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 pharma- ceutically acceptable salt thereof.

[0522] 143. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, 114 or 142, wherein the patient is suffering from negative thinking, and improvement in negative thinking is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0523] 144. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 113, 114, 142 or 143, wherein the patient is suffering from negative thinking, and improvement in negative thinking is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0524] 145. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 113, 114 or 142 to 144, wherein the patient is suffering from negative thinking, and improvement in negative thinking is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0525] 146. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 113, 114 or 142 to 145, wherein the patient is suffering from negative thinking, and improvement in negative thinking is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0526] 147. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 112, wherein the patient is suffering from negative thinking, and an improvement in negative thinking, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0527] 148. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 147, wherein the improvement in negative thinking as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0528] 149. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 147, wherein the improvement in negative thinking as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0529] 150. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 147, wherein the improvement in negative thinking as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0530] 151. 5-MeO-DMT or a pharma- ceutically 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.

[0531] 152. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, wherein said reduction or elimination of anxiety is reflected by at least an improvement in the score on the BDRS anxiety item 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0532] 153. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151 or 152, wherein the reduction or elimination of anxiety is reflected by an improvement in the score on the BDRS anxiety item at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0533] 154. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 151 to 153, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BDRS anxiety item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0534] 155. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 151 to 154, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BDRS anxiety item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0535] 156. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 151 to 155, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BDRS anxiety item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0536] 157. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, wherein the reduction or elimination of anxiety, as reflected by an improvement in the score on the BDRS anxiety item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0537] 158. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BDRS anxiety item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0538] 159. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BDRS anxiety item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0539] 160. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 157, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BDRS anxiety item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0540] 161. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the BPRS anxiety item score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0541] 162. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 151 or 161, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BPRS anxiety item on the first day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0542] 163. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, 161 or 162, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BPRS anxiety item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0543] 164. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 151 or 161 to 163, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BPRS anxiety item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0544] 165. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 151 or 161 to 164, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BPRS anxiety item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0545] 166. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BPRS anxiety item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0546] 167. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BPRS anxiety item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0547] 168. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BPRS anxiety item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0548] 169. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 166, wherein the reduction or elimination of anxiety as reflected by an improvement in the score on the BPRS anxiety item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0549] 170. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0550] 171. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151 or 170, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0551] 172. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151, 170 or 171, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0552] 173. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151 or 170 to 172, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0553] 174. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 151 or 170 to 173, wherein the patient suffers from anxiety, and improvement in anxiety is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0554] 175. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 150, wherein the patient is suffering from anxiety and the improvement in anxiety as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0555] 176. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0556] 177. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0557] 178. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 175, wherein the improvement in anxiety as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0558] 179. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 178, wherein the patient is suffering from cognitive impairment and the treatment reduces or eliminates the cognitive impairment.

[0559] 180. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 179, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in scores on the BDRS concentration and memory impairment items about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0560] 181. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179 or 180, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the scores on the BDRS concentration and memory impairment items at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0561] 182. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 179 to 181, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the scores on the BDRS concentration and memory impairment items 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0562] 183. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 179 to 182, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the scores on the BDRS concentration and memory impairment items 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0563] 184. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 179 to 183, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the scores on the BDRS concentration and memory impairment items 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0564] 185. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179, wherein the reduction or elimination of the cognitive impairment as reflected by an improvement in the scores on the BDRS concentration and memory impairment items occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0565] 186. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 185, wherein the reduction or elimination of the cognitive impairment as reflected by improvement in the scores on the BDRS concentration and memory impairment items persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0566] 187. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 185, wherein the reduction or elimination of the cognitive impairment as reflected by improvement in the scores on the BDRS concentration and memory impairment items persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0567] 188. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 185, wherein the reduction or elimination of the cognitive impairment as reflected by improvement in the scores on the BDRS concentration and memory impairment items persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0568] 189. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the MADRS concentration difficulties item score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0569] 190. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179 or 189, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the score on the MADRS difficulty concentrating item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0570] 191. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179, 189 or 190, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the score on the MADRS difficulty concentrating item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0571] 192. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 179 or 189 to 191, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the score on the MADRS difficulty concentrating item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0572] 193. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 179 or 189 to 192, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the score on the MADRS difficulty concentrating item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0573] 194. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 179, wherein the reduction or elimination of the cognitive impairment as reflected by an improvement in the score on the MADRS difficulty concentrating item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0574] 195. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 194, wherein the reduction or elimination of the cognitive impairment as reflected by an improvement in the score on the MADRS difficulty concentrating item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0575] 196. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 194, wherein the reduction or elimination of the cognitive impairment as reflected by an improvement in the score on the MADRS difficulty concentrating item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0576] 197. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 194, wherein the reduction or elimination of the cognitive impairment as reflected by an improvement in the score on the MADRS difficulty concentrating item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0577] 198. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 179, wherein the patient is suffering from cognitive impairment, and improvement of the cognitive impairment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0578] 199. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 179 or 198, wherein the patient is suffering from cognitive impairment, and improvement of the cognitive impairment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0579] 200. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 179, 198 or 199, wherein the patient is suffering from cognitive impairment, and improvement of the cognitive impairment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0580] 201. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 179 or 198 to 200, wherein the patient is suffering from cognitive impairment, and improvement of the cognitive impairment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0581] 202. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 179 or 198 to 201, wherein the patient is suffering from cognitive impairment, and improvement of the cognitive impairment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0582] 203. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 178, wherein the patient is suffering from cognitive impairment, and an improvement in the cognitive impairment as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0583] 204. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 203, wherein the improvement in cognitive impairment as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0584] 205. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 203, wherein the improvement in cognitive impairment as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0585] 206. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 203, wherein the improvement in cognitive impairment as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0586] 207. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 206, wherein the patient suffers from social / emotional withdrawal or isolation, and the treatment reduces or eliminates the social / emotional withdrawal or isolation.

[0587] 208. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, wherein said treatment reduces or eliminates at least one of anhedonia, emotional withdrawal and affective flattening.

[0588] 209. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207 or 208, wherein the reduction or elimination of social / emotional withdrawal or detachment is reflected by at least an improvement in scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0589] 210. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207 to 209, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0590] 211. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207 to 210, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0591] 212. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207 to 211, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0592] 213. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207 to 212, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0593] 214. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207 or 208, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0594] 215. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 214, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattening of affect items persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0595] 216. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 214, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattening of affect items persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0596] 217. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 214, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the scores on the BDRS anhedonia, emotional withdrawal and / or flattened affect items persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0597] 218. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207 or 208, wherein the reduction or elimination of said social / emotional withdrawal or estrangement is reflected by at least an improvement in the pre-score on the MADRS Unable to Have Emotions item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0598] 219. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208 or 218, wherein the reduction or elimination of the social / emotional withdrawal or estrangement is reflected by at least an improvement in the score on the MADRS Unable to Feel item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0599] 220. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208, 218 or 219, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the score on the MADRS Unable to Feel item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0600] 221. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 218-220, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the score on the MADRS Inability to Have Emotions item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0601] 222. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 218 to 221, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the score on the MADRS Unable to Feel item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0602] 223. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207 or 208, wherein the reduction or elimination of the social / emotional withdrawal or detachment, as reflected by an improvement in the score on the MADRS Unable to Feel item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0603] 224. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 223, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the MADRS Unable to Feel item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0604] 225. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 223, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the MADRS Unable to Feel item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0605] 226. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 223, wherein the reduction or elimination of the social / emotional withdrawal or estrangement as reflected by an improvement in the score on the MADRS Unable to Feel item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0606] 227. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207 or 208, wherein the reduction or elimination of said social / emotional withdrawal or estrangement is reflected by at least an improvement in the score on the BPRS emotional withdrawal item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0607] 228. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208 or 227, wherein the reduction or elimination of the social / emotional withdrawal or estrangement is reflected by at least an improvement in the score on the BPRS emotional withdrawal item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0608] 229. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208, 227 or 228, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the score on the BPRS emotional withdrawal item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0609] 230. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 227-229, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected by at least an improvement in the score on the BPRS emotional withdrawal item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0610] 231. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 227-230, wherein the reduction or elimination of the social / emotional withdrawal or estrangement is reflected by at least an improvement in the score on the BPRS emotional withdrawal item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0611] 232. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207 or 208, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS emotional withdrawal item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0612] 233. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 232, wherein the reduction or elimination of the social / emotional withdrawal or estrangement as reflected by an improvement in the score on the BPRS emotional withdrawal item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0613] 234. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 232, wherein the reduction or elimination of the social / emotional withdrawal or estrangement as reflected by an improvement in the score on the BPRS emotional withdrawal item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0614] 235. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 232, wherein the reduction or elimination of the social / emotional withdrawal or estrangement as reflected by an improvement in the score on the BPRS emotional withdrawal item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0615] 236. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207 or 208, wherein the reduction or elimination of said social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the BPRS blunted affect item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0616] 237. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208 or 236, wherein the reduction or elimination of the social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the BPRS Affective Bluntness item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0617] 238. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 207, 208, 236 or 237, wherein the reduction or elimination of the social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the BPRS blunted affect item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0618] 239. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 236 to 238, wherein the reduction or elimination of the social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the BPRS blunted affect item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0619] 240. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 207, 208 or 236-239, wherein the reduction or elimination of the social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the BPRS blunted affect item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0620] 241. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207 or 208, wherein the reduction or elimination of the social / emotional withdrawal or detachment, as reflected by an improvement in the score on the BPRS Blunted Affect item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0621] 242. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 241, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Blunted Affect item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0622] 243. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 241, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Blunted Affect item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0623] 244. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 241, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Blunted Affect item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0624] 245. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207 or 208, wherein the patient suffers from social / emotional withdrawal or isolation, and improvement in social / emotional withdrawal or isolation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0625] 246. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207, 208 or 245, wherein the patient suffers from social / emotional withdrawal or isolation, and improvement in social / emotional withdrawal or isolation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0626] 247. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207, 208, 245 or 246, wherein the patient suffers from social / emotional withdrawal or isolation, and improvement in social / emotional withdrawal or isolation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0627] 248. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207, 208 or 245 to 247, wherein the patient suffers from social / emotional withdrawal or isolation, and improvement of the social / emotional withdrawal or isolation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0628] 249. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 207, 208 or 245 to 248, wherein the patient suffers from social / emotional withdrawal or detachment, and improvement of the social / emotional withdrawal or detachment is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0629] 250. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 206, wherein the patient suffers from social / emotional withdrawal or detachment, and at least an improvement in the social / emotional withdrawal or detachment, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0630] 251. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 250, wherein the improvement in social / emotional withdrawal or detachment, as reflected by at least a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0631] 252. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 251, wherein the improvement in social / emotional withdrawal or detachment, as reflected by at least a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0632] 253. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 251, wherein the improvement in social / emotional withdrawal or detachment, as reflected by at least a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0633] 254. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 253, wherein said treatment reduces or eliminates suicidal thoughts.

[0634] 255. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the BDRS suicidal ideation item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0635] 256. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 254 or 255, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the BDRS suicidal ideation item on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0636] 257. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 254 to 256, wherein the reduction or elimination of suicidal ideation is reflected at least by an improvement in the score on the BDRS suicidal ideation item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0637] 258. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 254 to 257, wherein the reduction or elimination of suicidal ideation is reflected at least by an improvement in the score on the BDRS suicidal ideation item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0638] 259. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 254 to 258, wherein the reduction or elimination of suicidal ideation is reflected at least by an improvement in the score on the BDRS suicidal ideation item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0639] 260. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, wherein the reduction or elimination of suicidal ideation, as reflected by an improvement in the score on the BDRS suicidal ideation item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0640] 261. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 260, wherein the reduction or elimination of suicidal ideation, as reflected by an improvement in the score on the BDRS suicidal ideation item, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0641] 262. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 260, wherein the reduction or elimination of suicidal ideation, as reflected by an improvement in the score on the BDRS suicidal ideation item, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0642] 263. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 260, wherein the reduction or elimination of suicidal ideation, as reflected by an improvement in the score on the BDRS suicidal ideation item, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0643] 264. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the MADRS suicidal thoughts item score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0644] 265. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254 or 264, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the MADRS suicidal thoughts item at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0645] 266. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, 264 or 265, wherein the reduction or elimination of suicidal ideation is reflected at least by an improvement in the score on the MADRS suicidal thoughts item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0646] 267. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 254 or 264 to 266, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the MADRS suicidal thoughts item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0647] 268. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 254 or 264 to 267, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the MADRS suicidal thoughts item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0648] 269. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, wherein the reduction or elimination of suicidal ideation, as reflected by an improvement in the score on the MADRS suicidal thoughts item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0649] 270. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the score on the MADRS suicidal thoughts item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0650] 271. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the score on the MADRS suicidal thoughts item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0651] 272. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 269, wherein the reduction or elimination of suicidal ideation as reflected by an improvement in the score on the MADRS suicidal thoughts item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0652] 273. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, wherein the patient is suffering from suicidal ideation, and improvement in suicidal ideation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0653] 274. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254 or 273, wherein the patient is suffering from suicidal ideation, and improvement in suicidal ideation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0654] 275. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254, 273 or 274, wherein the patient is suffering from suicidal ideation, and improvement in suicidal ideation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0655] 276. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254 or 273 to 275, wherein the patient is suffering from suicidal ideation, and improvement in suicidal ideation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0656] 277. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 254 or 273 to 276, wherein the patient is suffering from suicidal ideation, and improvement in suicidal ideation is reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0657] 278. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 253, wherein the patient is suffering from suicidal ideation, and an improvement in suicidal ideation, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0658] 279. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 278, wherein the improvement in suicidal ideation as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0659] 280. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 278, wherein the improvement in suicidal ideation as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0660] 281. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 278, wherein the improvement in suicidal ideation as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0661] 282. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 281, wherein said treatment reduces or eliminates at least one of psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation. EXAMPLES

[0662] The following examples are included to aid in the understanding of the invention and are not intended, and should not be construed as, limiting the invention, as set forth in the claims which follow, in any manner.

[0663] Example 1-5 - MeO-DMT aerosol generation and administration Step 1: A stock solution of 5-MeO-DMT free base in 100% ethanol is prepared in a volumetric flask such that the target dosage of 5-MeO-DMT free base to be administered to a volunteer or patient via inhalation is contained in a solution volume of 200 μl. A typical target dosage is 1 mg to 25 mg of 5-MeO-DMT. For example, for a target dosage of 18 mg of 5-MeO-DMT, 90 mg of 5-MeO-DMT is dissolved in 100% ethanol for a final solution volume of 1 ml. An aliquot of the stock solution may then be stored in a vial until further use.

[0664] Step 2: 200 μl of the solution is transferred into a dosing capsule containing an infusion pad (Storz & Bickel, Germany) and the dosing capsule is then closed.

[0665] Step 3: The dosing capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of the first Volcano Medic Vaporizer, preheated at a temperature set at 55°C. The vaporizer airflow is then turned on for 60 seconds at a preset rate of approximately 12 l / min. The heated air flows through the dosing capsule, allowing the ethanol to evaporate, leaving the target dosage of 5-MeO-DMT within the capsule as a thin layer covering the stainless steel wire mesh. Correct preparation of the dosing capsule can be confirmed by demonstrating that the final weight gain of the capsule compared to the weight of the empty capsule is approximately equal to the target dosage of 5-MeO-DMT.

[0666] Step 4: The prepared dose capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which is preheated at a temperature set at 210° C. and has the airflow turned on for at least 5 minutes and then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is attached to the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately thereafter turned on for exactly 15 seconds at a preset flow rate of about 12 l / min and then turned off. This aerosolizes the entire dose of 5-MeO-DMT and disperses it in the approximately 3 liters of air in the inhalation balloon. It can be confirmed that the 5-MeO-DMT has been accurately aerosolized by demonstrating that the capsule's weight has returned approximately to its initial weight.

[0667] Step 5: The balloon is then removed from the filling chamber, the valve automatically closes, a mouthpiece is attached to the balloon and the aerosol is ready to be administered immediately to a volunteer or patient.

[0668] Step 6: To prepare for administration, the patient is asked to first take 1-2 deep inhalations and complete exhalations, concluding this sequence with a deep exhalation. Then, holding the mouthpiece firmly against the lips, inhale the entire volume of the inhalation balloon completely in one inhalation, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, the patient is instructed to lie down.

[0669] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO2020 / 169850A1, the contents of which are incorporated herein by reference.

[0670] Example 2 - Preparation of 5-MeO-DMT in high purity 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 vol) at 35-40° C. and then cooled to room temperature over 30 min. After stirring at room temperature for 50 min, no crystallization was observed, so the batch temperature was reduced to 7-12° C. over 30 min. Crystallization occurred after stirring at 7-12° C. for 10 min. The batch was then stirred at 7-12° C. for 1 h before being filtered. After washing with MTBE (1 mL, 0.5 vol.) at 7-12° C., the batch was dried under vacuum for 3.5 h to produce a pale orange solid in 1.02 g (50% recovery). The isolated solid was analyzed for purity by HPLC as described in WO2020 / 169850A1. The purity was found to be 99.74% area.

[0671] The analysis further indicates that the levels of individual impurities were less than 0.10% area. Solvent analysis of the sample showed an MTBE level of 17 ppm.

[0672] Example 3-5—Preparation of MeO-DMT Hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0673] The free base of 5-MeO-DMT was combined with isopropyl acetate (10 volumes) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr was charged in a single aliquot (1 M in ethanol, 1 equivalent). The mixture was maintained at temperature and equilibrated for 3 hours.

[0674] After 1 hour, a suspension formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried under vacuum at 40° C. for 18 hours.

[0675] An off-white crystalline material was obtained.

[0676] The salt has a melting point of 174 °C and is characterized by an X-ray diffraction pattern measured with Cu K· radiation, containing 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·; and 27.4°2·±0.2°2·.

[0677] Example 4 - Determination of inhibition constants of central 5-HT1A and 5-HT2A receptors in postmortem human brain membrane preparations In this study, the affinity of three hallucinogenic test compounds (psilocin, DMT and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue from the hippocampus and frontal cortex, respectively, was determined using radioligand binding techniques.

[0678] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors had died suddenly, had no history of coma, psychiatric or neurological disorders, were under 65 years of age, and samples were obtained within 72 hours of death.

[0679] Binding to 5-HT1A receptors in postmortem human hippocampus The hippocampi were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice and the pellet was rehomogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold membrane preparation buffer (1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 min, followed by centrifugation at 20,500 g for 10 min. The pellet was resuspended and centrifuged a final time (20,500xg, 10 min) to wash the tissue. The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equivalent to 3.125 mg wet weight tissue / ml. All centrifugations were performed at 4°C. Membrane preparation buffer consisted of 50 mM Tris-HCl (pH 7.7), 4 mM CaCl2, and 0.1% ascorbic acid. Assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM pargyline.

[0680] For saturation binding analysis, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were diluted with 50 μl of 0.075–9.6 nM [ 3 H]8-OH-DPAT was incubated with either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY100635 (non-specific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0681] For the displacement assay, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μl of 0.6 nM [ 3H]8-OH-DPAT was incubated for 30 min at 25°C with either 50 μl of assay buffer (total binding) or 50 μl of 1·M WAY100635 (nonspecific binding) or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10000 nM.

[0682] Membrane-bound radioactivity was harvested by filtration under vacuum through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. Filters were washed briefly with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity determined by liquid scintillation counting (1 ml Packard MV gold scintillator).

[0683] The concentration of compound required to inhibit 50% of the specific binding (IC 50 ) and Hill Slope were calculated by using nonlinear regression. K i was calculated.

[0684] Binding to 5-HT2A receptors in postmortem human frontal cortex Frontal cortices were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice and the pellet was rehomogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was centrifuged two more times to wash the tissue (20,500 x g for 10 min). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, at a tissue concentration equivalent to 10 mg wet weight tissue / ml. All centrifugations were performed at 4°C.

[0685] For saturation binding analysis, frontal cortex membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were diluted with 50 μl of 0.00625–0.8 nM [ 3 H]MDL-100,907 was incubated with either 50 μl of assay buffer or 50 μl of 10 M ketanserin (nonspecific binding) for 60 min at 25°C. Assay and wash buffer consisted of 50 mM Tris-HCl buffer pH 7.4.

[0686] For the displacement assay, frontal cortical membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were incubated for 60 min at 25°C 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·M ketanserin (nonspecific binding) or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10000 nM.

[0687] Membrane-bound radioactivity was harvested and measured as above, and data analysis was also as above.

[0688] result [5-HT1A receptor activity in hippocampal membranes from postmortem human brain tissue] 3 Dissociation constant of 8-OH-DPAT (K d The dissociation constants (K d The concentrations of 0.51, 0.28 and 0.52 nM, respectively.

[0689] The average inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0690] [5-HT2A receptor activity in frontal cortex membranes from postmortem human brain tissue] 3 Dissociation constant of H]MDL-100,907 (K d The dissociation constants (K d The concentrations of 0.11, 0.08 and 0.08 nM, respectively.

[0691] The average inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0692] The selectivity ratios of psilocin, DMT and 5-MeO-DMT for the 5-HT2A receptor versus the 5-HT1A receptor were 0.78, 3.1 and 68, respectively.

[0693] Example 5 - Clinical Trial in Patients Affected by TRD A Phase 1 / 2 clinical trial of 5-MeO-DMT, administered by inhalation as described herein, in patients with treatment-resistant major depressive disorder (TRD) has been completed. The study was designed in two parts. Part A was an open-label, single-arm, single-dose Phase 1 study with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B was an open-label, single-arm, Phase 2 study applying an individualized dosing schedule with intrapatient dose escalation with 5-MeO-DMT. Patients (n=8) received at least one and up to three doses (6 mg, 12 mg, and 18 mg) of 5-MeO-DMT in a single day, with higher doses administered only if a peak experience was not achieved with the previously administered dose. The primary endpoint of Part A was to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in patients with TRD. The primary endpoint of Part B was to evaluate the effect on depression severity, as measured by the proportion of patients in remission (defined as a MADRS total score of 10 or less) at 7 days after dosing.

[0694] In Part A, 3 of 4 patients in both arms (12 mg and 18 mg) experienced at least 1 ADR, all of which were mild and resolved spontaneously. No SAEs were reported.

[0695] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS resolution at day 7 after dosing, and one additional patient (25%) in the 18 mg group had a MADRS clinical response at day 7 after dosing. The mean MADRS percent change from baseline at day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0696] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0697] The primary endpoint was met, with 7 of 8 patients (87.5%) achieving MADRS remission at day 7 (p<0.0001). The mean MADRS change from baseline at day 7 was 24.4 (76%).

[0698] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or cognitive function measures in either Part A or Part B.

[0699] The results are summarized in the table below.

[0700] [Table 1]

[0701] [Table 2]

[0702] [Table 3]

[0703] [Table 4]

[0704] [Table 5]

[0705] [Table 6]

[0706] Example 6-5 - Pharmacokinetic evaluation of MeO-DMT and bufotenin To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups containing eight subjects each were formed. Subjects received a single dose of 6 mg; 12 mg or 18 mg of 5-MeO-DMT by inhalation. Blood samples were obtained at 1; 2; 4; 7; 10; 15; 20; 30; 45 min and 1; 1.5; 2; 3; 4 h after administration.

[0707] 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.

[0708] The median Cmax values ​​obtained in 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).

[0709] Table 3 below shows the median plasma concentration percentages of Cmax measured at the indicated time points.

[0710] [Table 7]

[0711] Pharmacokinetic measurements were also performed for a dosing scheme that relied on ascending titration, with substantially similar results.

[0712] We also measured plasma concentrations of the 5-MeO-DMT metabolite bufotenine. In only a few samples were concentrations above the lower level of quantification (LLOQ) (25 pg / ml). After 15 min, bufotenine concentrations were always below the LLOQ.

[0713] Substantially similar observations were made when subjects who received an escalating titration scheme were included.

[0714] Example 7-5-MeO-DMT Toxicity Test 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 with concentrations up to 5000 μg / plate (the maximum recommended concentration according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

[0715] Example 8 - Clinical trial of inhaled 5-MeO-DMT in patients with postpartum depression The single-arm, open-label clinical trial will enroll 15 adult female patients with a clinical diagnosis of postpartum depression (PPD).

[0716] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0717] More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0 (6 mg, 12 mg, and 18 mg).

[0718] 1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT. 2. The second dose (12 mg) is administered only if: a. Failure to achieve a peak experience (total score of 75) after administration of 6 mg; and b. If the 6 mg dose is deemed safe and well tolerated by the investigator, c. Any psychoactive effects (PsE) from the previous dose have subsided; and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or outside the normal range but not considered clinically significant by the investigator. 3. Similarly, the third dose (18 mg) is administered only if: a. Failure to achieve a peak experience (total score of 75) after administration of 12 mg; and b. The 12 mg dose is deemed safe and well tolerated by the investigator, and c. Any PsE from the previous dose has subsided; and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or outside the normal range but not considered clinically significant by the investigator.

[0719] Patients will be assessed for hallucinogenic climax experiences (based on a patient-scored visual analog scale, the PE scale), sedation, and other endpoints after dosing. Follow-up visits are scheduled 1 and 7 days after dosing.

[0720] All patients considered for participation in a clinical trial must meet the following criteria: 1. Female, aged 18-45 years (inclusive) at the time of screening. 2. 18.5-35 kg / m at screening 2 Have a body mass index (BMI) in the (inclusive) range. 3. Meets the study criteria for PPD as assessed by a study psychiatrist or registered psychologist: A diagnosis of major depressive disorder without psychotic features as confirmed by the Mini International Neuropsychiatric Interview (MINI) with perinatal onset occurring after conception and up to the first 4 weeks after delivery. b. Having a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 28 or greater at screening and pre-dosing on day 0; 6. Must have discontinued breastfeeding at the time of screening, or if still lactating or actively breastfeeding at screening, agree to temporarily discontinue breastfeeding from just before study drug administration on Day 0 through 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24 hour period, but which must incorporate expression / discarding at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding. 4. Patients must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use a highly effective (failure rate <1%) medically acceptable method of contraception for 30 days prior to and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test at screening and the day before the study (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medication until after the end of the study on Day 7 and agree to keep any psychotherapy unchanged during the study.

[0721] Candidate patients who meet any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past bipolar disorder, manic or hypomanic episodes, psychotic disorder, major depressive disorder (MDD) or other mood disorder 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 comorbid psychiatric illness that would cause the investigator to determine that the patient is unsuitable for the study. 2. Have one or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD). 3. At significant risk based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as determined by a study psychiatrist or registered psychologist. 4. Receiving antidepressant medication within 14 days or 5 half-lives (whichever is longer) prior to dosing (exception: within the past 5 weeks for fluoxetine). 5. Having received any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Previously experienced a significant adverse reaction to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the study physician. 7. Have a known allergy or hypersensitivity or any other contraindication to 5-MeO-DMT. 8. Any current or past clinically significant medical condition that would cause the study physician to determine that the patient is unsuitable for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of a hypertensive disorder of pregnancy during or after delivery (e.g., gestational hypertension, preeclampsia-eclampsia, aggravated preeclampsia), uncontrolled diabetes mellitus, severe cardiovascular disease, severe liver or renal failure, severe brain disorder (including seizure disorders, stroke, dementia, degenerative neurological disease, meningitis, encephalitis, and head injury with loss of consciousness). 9. The patient is receiving any medication or other substance that would cause the investigator to determine that the patient is unsuitable for the study. 10.Has clinically significant abnormalities in physical exam, vital signs, ECG, or clinical laboratory parameters that would cause the study physician to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day before the study (day -1) are pregnant or intend to become pregnant during the study and up to 90 days after 5-MeO-DMT administration. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0722] The primary objective of this study is to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg of 5-MeO-DMT in adult female patients with PPD.

[0723] Secondary objectives are to determine the antidepressant and anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE), and effects on cognitive outcomes of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0724] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood and urine by LC / MS / MS measurement after daily IDR doses of 6 mg, 12 mg and 18 mg of 5-Meo-DMT in adult female patients with PPD (metabolite identity screening may be performed if necessary).

[0725] The primary endpoint of this study was the antidepressant effect of 5-MeO-DMT as measured by the change from baseline in the MADRS assessed at day 7.

[0726] Secondary endpoints include the antidepressant effects of 5-MeO-DMT, as assessed by: Antidepressant effects of 5-MeO-DMT as assessed by: o Proportion of patients in remission (MADRS·10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Change from baseline in the MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; o Proportion of responders (reduction from baseline in MADRS total score of 50%) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; ○ Change from baseline in the Clinical Global Impression-Severity scale (CGI-S) 2 hours after the last dose of study medication on Day 0, and on Days 1 and 7; Effects on maternal behavior as assessed by change from baseline in Barkin Index of Maternal Functioning (BIMF) total and subscale scores by day 7; · 5-MeO-DMT and bufotenin exposure in breast milk obtained the day before the study (day -1), 1 hour after the last study drug administration, at discharge, in the evening of day 0, and on days 1 and 7; · 5-MeO-DMT and bufotenine exposure in blood obtained the day before the study (day -1), 1 hour after the last study drug administration, at discharge, and on days 1 and 7; Safety and tolerability of 5-MeO-DMT as assessed by: o Reporting of treatment-emergent adverse events (TEAEs); o Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak expiratory flow measurements; o Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each study drug administration) and as part of the discharge assessment on Day 0; o Change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS), assessed as part of the discharge assessment on day 0 and on days 1 and 7; o Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed as part of the discharge assessment on day 0 and on days 1 and 7; o Change from baseline in C-SSRS assessed as part of the discharge assessment on day 0 and on days 1 and 7; o Change from baseline in the YMRS, assessed as part of the discharge assessment on day 0 and on days 1 and 7; 30-60 minutes after each dose, when the PsE subsided, patients reported experiencing: o PsE assessment using the Peak Experience (PE) scale to assess PE achievement (PE total score·75); o Challenging Experiences Questionnaire (CEQ); o Mystical Experiences Questionnaire (MEQ-30); Duration of PsE, defined as the time from administration of study drug to the point at which PsE subsided (as scored by the study physician and the patient) (ending 30–60 minutes after each dose).

[0727] So far, one patient with postpartum depression diagnosed by a psychiatrist has been included in the clinical trial. The diagnosis was major depressive disorder without psychotic features, confirmed by the Mini International Neuropsychiatric Interview (MINI) (v7.0.2), with perinatal onset occurring from conception onward and up to the first 4 weeks after delivery. The patient was diagnosed with postpartum depression after the delivery of her third child. The patient completed all scheduled visits. The inhalation procedure was performed appropriately by the patient and was well tolerated, with no inhalation-related adverse events.

[0728] result Except for a transient, clinically non-relevant increase in heart rate and blood pressure immediately following administration of 5-MeO-DMT, no other significant changes in vital parameters occurred. Evaluation of the ECG (3 hours after administration) and safety laboratory analyses (7 days), CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (crampy left abdominal pain and headache, both on day 0) were mild, short in duration, and resolved spontaneously by the end of the study.

[0729] Regarding the intensity of the hallucinatory experience, the recorded PES score achieved by exposure to the 6 mg nominal dose was 17.3. This score indicated the need to proceed to the administration of a higher subsequent dose of 12 mg, according to the individualized dosing plan design. The PES score achieved at this dose was 85.7, which was 75, indicating that the patient had experienced a hallucinatory peak experience and completed the IDR.

[0730] Importantly, this patient reported a significant improvement in depressive symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and this improvement was maintained over time (Table 4). This patient also met standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score ≤10).

[0731] [Table 8-1] [Table 8-2]

[0732] In particular, significant improvements were observed on several MADRS items, which are outlined in Table 4. Patients' baseline scores reflected the absence of symptoms on some items (loss of appetite, difficulty concentrating, suicidal thoughts), whereas scores reflecting severe symptoms (e.g., decreased sleep, inner tension) showed marked improvement.

[0733] Similarly, improvements were seen in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt and tension.

[0734] Summary and Conclusion A. An individualized dosing regimen of 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT administered by inhalation was well tolerated and induced surprising and highly significant clinical responses in patients formally diagnosed with postpartum depression. B. This clinical response occurs rapidly, within 2 hours after administration of 5-MeO-DMT. Such rapid onset is unusual and has not been seen with previous classes of antidepressants, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRl), serotonin-norepinephrine reuptake inhibitors (SNRl), and others, which typically require 4-6 weeks to demonstrate their effects. C. Patients experienced clinical remission within 2 hours of 5-MeO-DMT administration according to the IDR, which is vastly superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date. D. Significant clinical responses were sustained over a 7-day follow-up period. However, 5-MeO-DMT was only administered once and is no longer effectively present in the body during this time frame (see pharmacokinetic data above). This observation supports the excellent clinical profile of 5-MeO-DMT and allows for convenient dosing intervals. E. In addition to the antidepressant effects, endpoints assessing other symptoms (e.g., hypochondriasis, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0735] The clearly demonstrated aspects demonstrate that 5-MeO-DMT, when used according to this dosing regimen, has a significantly improved efficacy profile compared to approved pharmacotherapies for postpartum depression and all hallucinogens tested to date.

[0736] Example 9 - Clinical trial of inhaled 5-MeO-DMT in patients with bipolar II disorder The single-arm, open-label clinical trial involved 15 adult patients with bipolar II disorder and a current major depressive episode.

[0737] Patients currently receiving antidepressant medications will need to discontinue or taper off such medications over time.

[0738] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0739] More specifically, patients will receive up to three doses (6 mg, 12 mg, and 18 mg) of 5-MeO-DMT on the day of administration (day 0).

[0740] 1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT. 2. The second dose (12 mg) is administered only if: a. Failure to achieve a peak experience (PES total score of 75) after administration of 6 mg; and b. If the 6 mg dose is deemed safe and well tolerated. 3. Similarly, the third dose (18 mg) is administered only if: a. Failure to achieve a peak experience (PES total score of 75) after administration of 12 mg; and b. The 12 mg dose is deemed safe and well tolerated.

[0741] Patients will be assessed for hallucinogenic climax experiences based on patient-scored PES, sedation, and other endpoints described above after dosing. Follow-up visits will be scheduled 1 and 7 days after dosing.

[0742] Patient selection was based on the following key inclusion criteria: 1. Understands the nature of the clinical trial and has provided signed and dated written informed consent in accordance with local regulations prior to the conduct of any study-related procedures. 2. Male or female, aged 18-64 years (inclusive) at the time of screening. 3. Meets study criteria for bipolar II disorder and has experienced a major depressive episode as assessed by a study psychiatrist or registered clinical psychologist: Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for bipolar II disorder with a current major depressive episode as confirmed by the Mini-International Neuropsychiatric Interview (MINI); b. Having a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 24 or greater at screening and prior to the first dose on Day 0; 4. Have a Young Mania Rating Scale (YMRS) total score of 8 or less at screening and prior to the first dose on Day 0; 5. Agree to maintain any psychiatric therapy unchanged and not to start any new psychoactive medication during the course of the study. 6. Female patients must be surgically sterile (hysterectomy, tubal ligation, or bilateral oophorectomy (6 months prior to screening)) or postmenopausal amenorrhea for the last 2 years, or remain completely abstinent (total abstention from heterosexual intercourse) or use a highly effective (failure rate <1%) medically accepted method of contraception (including but not limited to bilateral tubal ligation / occlusion, hormonal contraceptives that suppress ovulation, intrauterine devices (including hormone-releasing intrauterine devices / systems)) for 30 days prior to and 90 days after 5-MeO-DMT treatment, and have a negative serum pregnancy test at screening and a negative urine pregnancy test the day prior to the study (day -1). 7. Male patients must use preventive contraception (i.e., condoms with spermicide or abstinence) and must not donate sperm for 30 days after 5-MeO-DMT administration.

[0743] Candidate patients who meet any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past bipolar disorder, manic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorder 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 comorbid psychiatric illness that would cause the investigator to determine that the patient is unsuitable for the study. 2. Have one or more first or second degree relatives with a current or previously diagnosed psychotic disorder, bipolar I disorder, or MDD with psychotic features. 3. (a) suicidal ideation in the past year, during screening, or at baseline as identified by items 4 or 5 on the C-SSRS; or (b) suicidal behavior in the past year; or (c) clinical assessment of significant suicide risk during the clinical interview; or (d) having significant suicide risk as defined by nonsuicidal self-injury in the past year. 4. Receiving antidepressant medication within 7 days or 5 half-lives (whichever is longer) prior to dosing (exception: within the past 5 weeks for fluoxetine). 5.Having been receiving medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Receiving mood stabilizer therapy (e.g., lamotrigine, valproate, atypical antipsychotics) within 14 days (28 days for lithium) or 5 half-lives (whichever is longer) prior to dosing,...

Claims

1. A pharmaceutical composition for treating bipolar disorder in a patient, comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the bipolar disorder is bipolar type II disorder, the patient is currently suffering from a major depressive episode, and the 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously.

2. The pharmaceutical composition according to claim 1, wherein the patient has a total score of 20 or higher on the Montgomery-Asberg Depression Rating Scale (MADRS) prior to treatment, for example, 28 or higher prior to treatment, and particularly 35 or higher prior to treatment.

3. The pharmaceutical composition according to claim 1, wherein the bipolar disorder is a treatment-resistant form of bipolar II disorder.

4. The pharmaceutical composition according to claim 1, wherein the patient has a total score of 19 or higher on the Bipolar Depression Rating Scale (BDRS) before treatment, for example, 24 or higher before treatment, and particularly 37 or higher before treatment.

5. The pharmaceutical composition according to claim 1, wherein the patient has a total score of 8 or less on the Young's Mania Rating Scale (YMRS) before treatment.

6. The pharmaceutical composition according to claim 1 or 2, wherein 5-MeO-DMT or a salt thereof is administered in 1 to 6 doses within 24 hours.

7. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations.

8. The pharmaceutical composition according to claim 7, wherein each subsequent dose after the first dose is administered in a larger dose than the previous dose.

9. The pharmaceutical composition according to claim 7, wherein the patient receives subsequent administration unless he or she experiences a hallucinatory peak experience.

10. The pharmaceutical composition according to claim 8, wherein the interval between two administrations is approximately 1 to 4 hours, preferably 1 to 2 hours.

11. The pharmaceutical composition according to claim 9, wherein the manifestation of the hallucinatory peak experience is identified by achieving at least 60% of the maximum possible score on each of the four secondary scales (mystical, positive mood, transcendence of time and space, and inexpressibility) of the 30-item revised Mystical Experiences Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score on the Oceania Infinite (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 75 on the total score of the Peak Experience Scale (PES).

12. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous injection.

13. The pharmaceutical composition according to claim 1, wherein a clinical response, such as that reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, is observed at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 1, wherein a clinical response is observed approximately two hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is reflected by an improvement of at least 50% in the BDRS score or the MADRS score compared to the respective scores before treatment.

15. The pharmaceutical composition according to claim 1, wherein a clinical response is observed at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is reflected by an improvement of at least 50% in the BDRS score or the MADRS score compared to the respective scores before treatment.

16. The pharmaceutical composition according to claim 1, wherein a clinical response is observed at least seven days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is reflected by an improvement of at least 50% in the BDRS score or the MADRS score compared to the respective scores before treatment.

17. The pharmaceutical composition according to claim 1, wherein a clinical response is observed at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is reflected in an improvement of at least 50% in the BDRS score or the MADRS score compared to the respective scores before treatment.

18. The pharmaceutical composition according to claim 1, wherein a clinical response is observed at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is reflected by an improvement of at least 75% in the BDRS score or the MADRS score compared to the respective scores before treatment.

19. The pharmaceutical composition according to claim 1, wherein the patient does not experience mania or hypomania that occurs as a result of the treatment.

20. The pharmaceutical composition according to claim 1, wherein the treatment improves at least one of the following: sleep disorders, psychomotor developmental delay, negative thinking, anxiety, cognitive impairment, and social / emotional withdrawal or isolation.

21. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a salt thereof is administered in a dose or dosage regimen sufficient to cause the patient to have a hallucinogenic peak experience.