5-Methoxy-N,N-dimethyltryptamine 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.

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 illness 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 mood elevation 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). Additionally, 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 modes of action. It has been suggested that several psychiatric disorders could in principle be amenable to treatment by psychoactive molecules such as hallucinogens.

[0022] However, psychedelic drugs have not been approved by any regulatory agency, and indeed the 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 in healthy subjects.

[0024] Against this background, it is an object of the present invention to provide a therapy which is more effective (i.e., a) has a greater percentage of patients experiencing a clinical response, b) has a greater mean clinical response, c) has a more rapid onset of clinical response, and / or d) has a more durable clinical response) than the previously described therapies.

[0025] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens thereof that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens thereof that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens thereof that are associated with higher patient compliance (including higher treatment initiation rates) than previously described therapies. A still further object of the present invention is to identify specific disease conditions and subgroups of specific disease conditions 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] 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 experience.

[0029] The administration is preferably by inhalation. For this purpose, an aerosol may be used, which comprises (a) a pharma- ceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l.

[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 specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is contemplated that pharma- ceutically acceptable salts of 5-MeO-DMT may also be 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 is diagnosed by a physician or psychologist using established protocols and methods for diagnosing suicidality. In general, it is not enough for the patient to believe that he or she is suffering from suicidal ideation. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of suicide or to have "intent to act."

[0041] As used in the context of the present invention, unless otherwise indicated, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, including the administration of compounds and the practice of 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 that 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, which biological or clinical response in humans includes 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-rated questionnaire that includes 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another suitable recall period.

[0050] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of time spent asleep and time spent asleep onset, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) time spent asleep onset, (3) duration of sleep, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleep medications, and (7) daytime functioning disorders.

[0051] Each component is assigned a score from 0 to 3. Higher scores indicate more acute sleep disturbance. Details of how the Pittsburgh Sleep Quality Index is scored 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 produce a single overall score ranging from 0 to 21 points, with "0" indicating no difficulties and "21" indicating severe difficulties in all areas. The cutoff value for the overall score is 5, which distinguishes between those with and without sleep problems. A total score of >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 occur no earlier than 12 hours after the last dose, and in any event no earlier than one night after the last dose and no later than 36 hours after the last dose. Evaluation may occur after about 24 hours.

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

[0063] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") is intended to mean the introduction of a possible amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered by nasal inhalation, by buccal administration or by sublingual administration.

[0064] As used in the context of the present invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" 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 "dosage regimen") is intended to mean a defined sequence of one or more individual administrations.

[0065] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharma- ceutically acceptable gas, such as air) and extremely small suspended solids and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When a percentage of "degradation products" is described in the context of the present invention, it refers to the amount of 5-MeO-DMT degradation products present in the sample divided by the amount of 5-MeO-DMT present in the sample plus the amount of 5-MeO-DMT degradation products present in the sample, multiplied by 100%, i.e., (sum of the amount of all 5-MeO-DMT degradation products present in the sample) / ((amount of 5-MeO-DMT present in the sample)+(sum of the amount of all 5-MeO-DMT degradation products present in the sample))×100%. As used herein, the term "impurities" refers to undesirable compounds that contaminate a 5-MeO-DMT (or a pharma-ceutically acceptable salt thereof) sample. The impurities may be contained in the starting material prior to formation of the aerosol, or the impurities may be decomposition products.

[0066] The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) / (the amount of 5-MeO-DMT present + the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0067] The term "mass median aerodynamic diameter" (MMAD) refers to a calculated diameter where 50% of the particles present in the aerosol are larger and 50% are smaller than that diameter. The term "aerosol particle mass concentration" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle generation rate" refers to the mass of aerosolized 5-MeO-DMT per unit time of aerosolization.

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

[0069] 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.

[0070] 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).

[0071] 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.

[0072] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated by trained raters for clinical use. BDRS items assess the severity of depressive and / or mixed symptoms exhibited by the patient during the current and past few days based on a clinical interview. In case of discrepancy between the current and past few days' symptoms, the current symptoms must be reflected in the rating. The scale includes 20 questions with a maximum score of 60. Higher scores indicate greater severity.

[0073] Questions address depressed mood, sleep disturbance, appetite disturbance, decreased social engagement, decreased energy and activity, decreased motivation, impaired concentration and memory, anxiety, anhedonia, flat affect, feelings of worthlessness, feelings of helplessness and hopelessness, suicidal thoughts, feelings of guilt, psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation.

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

[0075] Depressed mood is scored as 0 when there is no self-reported and / or observed depression as manifested by feelings of 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 significantly intense, pervasive, or persistent.

[0076] 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).

[0077] 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).

[0078] 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).

[0079] 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.

[0080] 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).

[0081] 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).

[0082] 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).

[0083] 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).

[0084] 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.

[0085] 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).

[0086] 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).

[0087] 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).

[0088] 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.

[0089] 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).

[0090] 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).

[0091] 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.

[0092] Sense of guilt (also simply called guilt) can be scored as 0 if there is no subjective sense of self-blame, failure, or regret for real or imagined past mistakes; 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.

[0093] 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).

[0094] 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.

[0095] 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.

[0096] 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).

[0097] 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.

[0098] 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).

[0099] Although higher scores on the BDRS scale indicate more severe symptoms, there are no universally accepted boundaries as to when a patient is to 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."

[0100] A variety of other measures are also useful for assessing disease severity as well as the clinical outcome of treatment.

[0101] The CGI was developed to provide 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).

[0102] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in this patient?" This is rated on a 7-point scale: 1 = normal (no illness at all), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, 7 = patients with very severe illness.

[0103] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0104] Alternatively, the success of the treatment can be evaluated using the CGI-Improvement (CGI-I), the format of which is similarly brief. After treatment, the clinician compares the patient's overall clinical condition with the condition 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 entry into the project (before starting medication), this patient's condition has improved 1=very much since starting treatment, 2=significantly improved, 3=minimally improved, 4=unchanged from baseline (at the start of treatment), 5=minimally worsened, 6=significantly worsened, 7=very much worsened since starting treatment."

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

[0106] 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 Depression Rating Scale (HAM-D) to make it more sensitive to changes brought about by antidepressants and other forms of medication. 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, inhibitions, 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).

[0107] 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).

[0108] 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.

[0109] 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 to assess 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.

[0110] The Brief Psychiatric Rating Scale (BPRS) aims to screen psychiatric symptoms in a structured manner. It 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 doctor 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).

[0111] 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, flat affect, excitement and disorientation) are scored and each item is rated on a scale of 1 to 7.

[0112] The doctor or psychologist completes two tasks during a 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.

[0113] The doctor or psychologist completes the BPRS form by ranking the severity of each domain on a scale of 1 to 7 based on the responses and observed behaviors. A score of 1 means no signs or symptoms, while the maximum score of 7 means signs or symptoms are present and severe. If a specific sign or symptom cannot be rated, a score of 0 or "no rating" is recorded.

[0114] 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).

[0115] 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.

[0116] 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 to globally evaluate the effectiveness of treatments related to suicidality. The C-SSRS is evidence-based 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).

[0117] The questionnaire will be administered as an interview by a licensed psychologist or physician.

[0118] 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).

[0119] The treatment also counteracts suicidal ideation. Furthermore, the treatment improves the mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0120] In particular, the present invention provides a method for treating depression in BD patients without inducing hypomania or mania.

[0121] Active Agent 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.

[0122] The inventors reasoned that carefully selected hallucinogens might improve the treatment of important aspects of BD and improve the disease overall.

[0123] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also called serotonin receptors (seven families, 5-HT1 to 5-HT7, with several subtypes, are described). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often called "hallucinogens" and highlight their primary ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), but with minimal other effects such as sedation, narcosis, or hyperstimulation.

[0124] Chemically, serotonergic hallucinogens are either phenylalkylamines or indolamines, the indolamines being divided into two subsets, the ergolines and tryptamines, the latter being derived from tryptamine.

[0125] 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.

[0126] 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.

[0127] 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 had a manic episode after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that then disappeared, but a typical manic episode of psychotic magnitude followed approximately 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a self-reported manic episode after ingesting 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 ayahuasca consumption in a man with bipolar disorder.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] As described in further detail in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin that is formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brains were i The inhibition constants (K values) of psilocin, DMT and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex 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.i The affinity (p < 0.05) for the 5-HT2A receptor is 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.

[0133] 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. As for psilocin and DMT, the contribution to 5-HT2A binding is increased compared to 5-MeO-DMT, and the latter of the three compounds has the largest difference between its affinity for 5-HT2A and 5-HT1A. Thus, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared to the other two compounds.

[0134] 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.

[0135] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered, preferably using the administration schemes described herein, to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes (e.g., 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 do not experience treatment-emergent mania or hypomania when treated according to the present invention.

[0136] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use seem to indicate that large amounts of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD) were used.

[0137] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0138] Furthermore, antidepressants have been reported to induce isolated hypomanic events 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.

[0139] 5-MeO-DMT can induce peak experiences (i.e. experiences characterized by a shift in emotional perspective described as "loss of self"), often leading 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 inhalation versus several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile that can be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0140] 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.

[0141] 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.

[0142] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered to BD patients using the administration schemes described herein without significant risk of inducing mania or hypomania.

[0143] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. 3H]LSD, and serotonin were used to estimate nonspecific binding, and K i was determined to be 2.3 nM.

[0144] Thus, in addition to the 5-HT1A and 5-HT2A receptors mentioned above, 5-MeO-DMT also interacts with the 5-HT7 receptor, for which it acts as an agonist and shows high (nanomolar) binding affinity.

[0145] 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.

[0146] 5-HT7 receptors are specifically expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and cerebellum.

[0147] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, especially those involving sleep disorders. Resting-state functional connectivity analysis in patients suffering from sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0148] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to its function in regulating the sleep / wake cycle, and the inventors believe that this makes it possible to treat patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0149] 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 with its "resetting" of functional network connectivity and neuroplasticity effects, contributes to the efficacy of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0150] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as well as to the 5-HT1A receptor, as two mediators of the effects of 5-MeO-DMT, including the "resetting" of the functional connectivity of the network and the neuroplasticity effects, allows it to exert a beneficial effect even in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor developmental retardation, negative thinking or social / emotional withdrawal, which is supported by the clinical results demonstrated in the studies referred to herein.

[0151] Another characteristic of 5-MeO-DMT is its short half-life.

[0152] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0153] The present inventors have investigated the pharmacokinetic properties of 5-MeO-DMT and found that inhaled 5-MeO-DMT was rapidly absorbed and distributed, with maximum concentrations and pharmacological effects observed during and shortly after administration.

[0154] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations drop very rapidly. Already 10 minutes after administration, concentrations are below 10% of Cmax, after 2 hours they are below 1% of Cmax, and after 3 hours 5-MeO-DMT is no longer detectable in plasma. This is true over the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. 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 dosing.

[0155] 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.

[0156] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0157] In accordance with the present invention, isotopic variants of 5-MeO-DMT and pharma- ceutically acceptable salts thereof may also be used. Where reference is made to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0158] Such variants are in particular deuterated forms of 5-MeO-DMT and pharma- ceutically acceptable salts of such forms.

[0159] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than would be expected based on the natural abundance of this isotope.

[0160] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced at one or more defined hydrogen positions.

[0161] 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.

[0162] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group.Even more examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms of the indole ring system.It should be noted that combinations of the above substitution patterns are also contemplated.

[0163] Methods for preparing these compounds are known in the art.

[0164] 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, as well as mixtures of salts of deuterated 5-MeO-DMT and salts of non-deuterated 5-MeO-DMT may also be used.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] An example of a suitable organic moiety is -C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 And each R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0169] A preferred example of an 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 as above.

[0170] Prodrugs, especially those of the above structure, can also be used in the form of pharma- ceutically acceptable salts.

[0171] 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).

[0172] Methods for preparing the prodrugs described herein are known in the art.

[0173] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0174] 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.

[0175] 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.

[0176] In one embodiment, the patient is diagnosed with bipolar II disorder. In another embodiment, the patient is diagnosed with bipolar I disorder.

[0177] Typically, whether diagnosed with bipolar II disorder or bipolar I disorder, the patient is experiencing a major depressive episode.

[0178] 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, especially 37 or greater.

[0179] 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.

[0180] 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.

[0181] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two adequate treatment courses. In particular, the patient has not shown sufficient improvement after at least two adequate treatment courses, where at least one of the two courses is drug therapy. For example, the patient has not shown sufficient improvement after at least two adequate drug therapy courses. At least two past treatment courses were administered especially during a depressive episode.

[0182] 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.

[0183] Treatment of BD As indicated above, the treatment methods according to the present invention address various aspects of bipolar disorder.

[0184] 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).

[0185] The treatment also counteracts suicidal ideation. Furthermore, the treatment improves the mixed symptoms (psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, agitation).

[0186] 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.

[0187] 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.

[0188] 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).

[0189] 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).

[0190] 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).

[0191] Clinical response may also be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least one grade. Preferably, a decrease in the CGI-S score of at least two grades and / or a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three grades and / or a score of 0.

[0192] 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.

[0193] 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.

[0194] 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. Of interest in the context of the present invention are those that received a single dose of 12 mg and those that received an intraday individualized dosing schedule (IDR), which allows for multiple ascending doses (6 mg, 12 mg and 18 mg) over the course of a day driven by the intensity of the patient-reported hallucinatory experience.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] In the aforementioned clinical trials involving administration of 5-MeO-DMT, the "decreased sleep" item of the MADRS (reflecting insomnia) was evaluated inter alia.

[0201] The MADRS "reduced sleep" item refers to the experience of a decreased duration or depth of sleep compared to a person's normal pattern when healthy. If the person sleeps normally, a score of 0 is assigned. A score of 2 reflects mild difficulty initiating sleep or mildly reduced, light, or interrupted sleep. A score of 4 means reduced or interrupted sleep for at least 2 hours. A score of 6 means less than 2-3 hours of sleep.

[0202] The combined MADRS "Decreased Sleep" item score across all eight patients in the study arm receiving the individualized dosing plan had a baseline of 25. By the first day of treatment (the earliest time point to assess the treatment's effect on sleep), the score had decreased to 12, corresponding to a 13-point or 52% improvement. By the seventh day of treatment, the score had decreased to 9, corresponding to a 16-point or 64% improvement.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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), the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0207] 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.

[0208] 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 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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).

[0218] In the clinical trials mentioned above involving administration of 5-MeO-DMT, the "inhibition" item of the MADRS was specifically evaluated.

[0219] "Restriction" refers to difficulty initiating or slowness in initiating and carrying out daily activities.

[0220] A score of 0 means that the patient has 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 simple activities that the patient normally does are difficult to start and require effort to perform. If the patient is completely inhibited and unable to do anything without assistance, a score of 6 is assigned.

[0221] This MADRS scale item is particularly relevant to psychomotor developmental delay (i.e., reduced energy and activity and reduced motivation).

[0222] The combined MADRS "inhibition" item score across all eight patients in the study arm receiving the individualized dosing regimen was 27 at baseline.

[0223] After 2 hours, the score decreased to 10, which corresponds to a 17-point or 63% improvement. After 1 day of treatment, the score decreased to 5, which corresponds to a 22-point or 81% improvement. After 7 days of treatment, the score decreased to 3, which corresponds to a 24-point or 89% improvement.

[0224] The combined MADRS "inhibition" item scores 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.

[0225] Thus, scores for the scale item "inhibition," which is particularly relevant to psychomotor developmental delay, are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat psychomotor developmental delay (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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] Alternatively or additionally, reduction or elimination of psychomotor developmental delay may be reflected by improvement in the MADRS inhibition 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.

[0230] The reduction or elimination of psychomotor developmental delay, as reflected by an improvement in the MADRS inhibition 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 an improvement in the MADRS inhibition 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] As indicated above, "reduced energy and activity" and "reduced 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 on the "inhibition" item of the MADRS will not only result in a correlated improvement in the scores on the "reduced energy and activity" and / or "reduced motivation" items of the BDRS scale, but will further contribute to an overall improvement in the BDRS score.

[0236] 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.

[0237] 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.

[0238] For the purposes of this document, these symptoms are grouped together as negative thoughts.

[0239] 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.

[0240] If there are no pessimistic thoughts, a score of 0 is assigned. If there are fluctuating thoughts of failure, self-blame, or self-depreciation, the score is 2. A score of 6 is assigned if there are persistent self-blame or clear but understandable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. If there are delusions of ruin, remorse, or irreparable guilt, and irrational, unwavering self-blame, a score of 6 is assigned.

[0241] The aggregate MADRS "pessimistic thinking" item score across all eight patients in the study arm receiving the individualized dosing regimen had a baseline of 28.

[0242] After 2 hours, the score decreased to 7, which corresponds to a 21 point or 75% improvement. After 1 day of treatment, the score decreased to 4, which corresponds to a 24 point or 86% improvement. After 7 days of treatment, the score decreased to 3, which corresponds to a 25 point or 89% improvement.

[0243] MADRS "pessimistic thinking" 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 8, corresponding to an 8-point or 50% improvement. On the first post-treatment day, the score had decreased to 7, corresponding to a 9-point or 56% improvement.

[0244] Seven days after treatment, the score decreased to 8, which corresponds to an 8 point or 50% improvement.

[0245] A BPRS item of particular relevance to guilt is "Guilt." This item concerns excessive preoccupation with or remorse for 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 something they have done or failed to do, but they are able to quickly shift their attention elsewhere. 5 - Moderately severe. Feelings of guilt, preoccupation with disappointing someone or failing at something, can focus attention elsewhere but only with great effort. Not delusional. 6 - Severe. Delusional guilt or irrational self-blame that is grossly out of proportion to the circumstances. Moderately distracted. 7 - Severe. Delusional feelings of guilt or irrational self-blame that are grossly out of proportion to the circumstances. The person is so preoccupied with the feelings of guilt that they may disclose to others or act on the delusion.

[0246] Aggregated BPRS "guilt" item scores across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 34.

[0247] After 3 hours, the score decreased to 14, which corresponds to a 20 point or 59% improvement. After 1 day of treatment, the score decreased to 11, which corresponds to a 23 point or 68% improvement. After 7 days of treatment, the score decreased to 10, which corresponds to a 24 point or 71% improvement.

[0248] Aggregated BPRS "guilt" item scores across all four patients in the 12 mg group had a baseline of 18.

[0249] After 3 hours, the score decreased to 9, which corresponds to a 9 point or 50% improvement. After 1 day of treatment, the score decreased to 5, which corresponds to a 13 point or 72% improvement. After 7 days of treatment, the score decreased to 5, which corresponds to a 13 point or 72% improvement.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] Improvement in negative thinking, 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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 anxiety. 2 - Very mild. Reports some discomfort due to more or less frequent worries than is normal for most healthy people. 3 - Mild. Worries frequently but can immediately shift attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily focus on other things, but does not interfere with functioning, or has occasional autonomic anxiety but does not interfere with functioning. 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety or some areas of functioning are impaired by anxiety or worry. 6 - Severe. Autonomic anxiety is present every day but not all day or many areas of functioning are impaired by anxiety or constant worry. 7- Severe. Autonomic anxiety is present consistently throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0265] Aggregated BPRS "anxiety" item scores across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 37.

[0266] After 3 hours, the score decreased to 19, which corresponds to an 18 point or 49% improvement. After 1 day of treatment, the score decreased to 16, which corresponds to a 21 point or 57% improvement. After 7 days of treatment, the score decreased to 17, which corresponds to a 20 point or 54% improvement.

[0267] Aggregated BPRS "anxiety" item scores across all four patients in the 12 mg group had a baseline of 25.

[0268] After 3 hours, the score decreased to 11, which corresponds to a 14 point or 56% improvement. After 1 day of treatment, the score decreased to 6, which corresponds to a 19 point or 76% improvement. After 7 days of treatment, the score decreased to 6, which corresponds to a 19 point or 76% improvement.

[0269] 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.

[0270] Thus, in accordance with the present invention, by treating a patient suffering from anxiety, the anxiety is reduced or eliminated.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] The MADRS item that is particularly relevant to concentration and memory problems is "Difficulty concentrating."

[0283] This item indicates difficulty in organizing one's thoughts and, in turn, a lack of ability to concentrate. If the patient concentrates effortlessly, the score is 0. If there is occasional difficulty in organizing one's thoughts, the score is 2. If there is difficulty concentrating or sustaining thoughts, leading to a reduced ability to read or carry on a conversation, a score of 4 is assigned. If the patient has great difficulty reading or carrying on a conversation, the score is 6.

[0284] The combined MADRS "difficulty concentrating" item score across all eight patients in the study arm receiving the individualized dosing regimen had a baseline of 30.

[0285] After 2 hours, the score decreased to 11, which corresponds to a 19-point or 63% improvement. After 1 day of treatment, the score decreased to 1, which corresponds to a 29-point or 97% improvement. After 7 days of treatment, the score decreased to 9, which corresponds to a 21-point or 70% improvement.

[0286] Aggregated MADRS "difficulty concentrating" item scores across all four patients in the 12 mg group had a baseline of 16.

[0287] After 2 hours, the score decreased to 7, which corresponds to a 9 point or 56% improvement. After 1 day of treatment, the score decreased to 2, which corresponds to a 14 point or 88% improvement. After 7 days of treatment, the score decreased to 3, which corresponds to a 13 point or 81% improvement.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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.

[0300] Anhedonia (the inability to experience pleasure) is recognised as a key symptom of bipolar disorder.

[0301] Scale items of particular relevance to social / emotional withdrawal or detachment are "inability to have feelings," "emotional withdrawal," and "flattened emotions." The first item is taken from the MADRS, the latter two appear in the BPRS.

[0302] The "inability to feel emotions" item on the MADRS reflects awareness of a diminished interest in the environment or in activities that are usually pleasurable. There is a diminished ability to respond emotionally to situations or people in the environment.

[0303] A score of 0 indicates a normal interest in surroundings and other people, while a score of 2 indicates a diminished ability to enjoy things that one would normally be interested in. A score of 4 is assigned if there is a loss of interest in surroundings and a 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.

[0304] 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. Lack of emotional engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but engages spontaneously with the interviewer most of the time. 3 - Mild. Lack of emotional engagement is indicated by a noticeable inability to provide feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4 - Moderate. Emotional contact is absent for much of the interview because the person is aloof, does not make eye contact, does not seem to care if the interviewer is listening, or may be preoccupied with psychotic content. 5 - Moderately severe. As in "4", but emotional contact is absent for the majority of the interview. 6 - Severe. Actively avoids emotional involvement. Often unresponsive or responds with yes / no (not due to paranoia alone). Responds with very little emotion. 7- Most severe. Consistently avoids emotional involvement. Does not respond or gives yes / no responses (not solely due to paranoia). May leave during interview or not respond at all.

[0305] The flat affect item of the BPRS concerns not only a restricted range of emotional expression in face, voice, and body language, but also a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- There is no flattening of emotions. 2 - Very mild. Emotional range is somewhat subdued or reserved, but displays appropriate facial and vocal expression within normal limits. 3-Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous appropriate emotional responses are not frequent. Voice tone is somewhat monotonous. 4 - Moderate. The range of affect is significantly reduced, the patient does not show emotion, smiles, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Usually, any expression or gesture is 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 are few, facial expression rarely changes, and the tone of voice is monotone most of the time. 6-Severe. Little range or expression of emotion. Speech and gestures are mechanical most of the time. Facial expressions are unchanged. Voice is monotone most of the time. 7- Most severe. Virtually no range or expression of emotion, stiff movements, monotonous tone of voice all the time.

[0306] The combined MADRS "inability to have emotions" item score across all eight patients in the study arm receiving the individualized dosing regimen had a baseline of 36.

[0307] After 2 hours, the score decreased to 12, which corresponds to a 24 point or 67% improvement. On the first day after treatment, the score decreased to 2, which corresponds to a 34 point or 94% improvement. On the seventh day after treatment, the score decreased to 6, which corresponds to a 30 point or 83% improvement.

[0308] When the BPRS "emotional withdrawal" item score was tallied, the baseline score was 13.

[0309] After 3 hours, the score was reduced to 8, which corresponds to a 5 point or 38% improvement. After 1 day of treatment, the score was reduced to 8, which corresponds to a 5 point or 38% improvement. After 7 days of treatment, the score was reduced to 8, which corresponds to a 5 point or 38% improvement.

[0310] When the BPRS "flattened affect" item score was tallied, the baseline score was 15.

[0311] After 3 hours, the score decreased to 11, which corresponds to an improvement of 4 points or 27%. After 1 day of treatment, the score decreased to 8, which corresponds to an improvement of 7 points or 47%. After 7 days of treatment, the score decreased to 8, which corresponds to an improvement of 7 points or 47%.

[0312] Aggregated MADRS "inability to have emotions" item scores across all four patients in the 12 mg group had a baseline of 16.

[0313] After 2 hours, the score dropped to 9, which corresponds to a 7 point or 44% improvement. After 1 day of treatment, the score dropped to 1, which corresponds to a 15 point or 94% improvement. After 7 days of treatment, the score dropped to 1, which corresponds to a 15 point or 94% improvement.

[0314] When the BPRS "emotional withdrawal" item score was compiled for the 12 mg group, the baseline score was 13.

[0315] After 3 hours, the score decreased to 11, which corresponds to a 2 point or 15% improvement. On the first day after treatment, the score decreased to 8, which corresponds to a 5 point or 38% improvement. On the seventh day after treatment, the score decreased to 6, which corresponds to a 7 point or 54% improvement.

[0316] When the BPRS "flattened affect" item score for the 12 mg group was compiled, the baseline score was 11.

[0317] After 3 hours, the score decreased to 8, which corresponds to a 3 point or 27% improvement. After 1 day of treatment, the score decreased to 6, which corresponds to a 5 point or 45% improvement. After 7 days of treatment, the score decreased to 5, which corresponds to a 6 point or 55% improvement.

[0318] 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 "flattened 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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.

[0325] 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.

[0326] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or isolation is reflected by at least an improvement in the score on the flattened BPRS Affective item 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.

[0327] The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the score on the flattened BPRS affect 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 social / emotional withdrawal or detachment, as reflected by an improvement in the score on the flattened BPRS affect 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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 "inability to have emotions" item score of the MADRS and the "emotional withdrawal" and "flat 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.

[0333] 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.

[0334] In the aforementioned clinical trials involving administration of 5-MeO-DMT, the "suicidal thoughts" item of the MADRS was specifically assessed.

[0335] "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.

[0336] 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 wishes they were dead, has frequent suicidal thoughts, and considers suicide as 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 to attempt suicide and / or is actively preparing for suicide.

[0337] This MADRS scale item is of particular relevance to suicidal ideation.

[0338] The combined MADRS "suicidal thoughts" item score across all eight patients in the study arm receiving the individualized dosing regimen was 11 at baseline.

[0339] After 2 hours, the score was reduced to 3, which corresponds to an 8 point or 73% improvement. After 1 day of treatment, the score was reduced to 1, which corresponds to a 10 point or 91% improvement. After 7 days of treatment, the score was reduced to 3, which corresponds to an 8 point or 73% improvement.

[0340] Aggregated MADRS "suicidal thoughts" item scores across all four patients in the 12 mg group had a baseline score of 8.

[0341] After 2 hours, the score decreased to 3, which corresponds to a 5 point or 63% improvement. On the first day after treatment, the score decreased to 5, which corresponds to a 3 point or 38% improvement. On the seventh day after treatment, the score decreased to 7, which corresponds to a 1 point or 13% improvement.

[0342] 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.

[0343] Thus, in accordance with the present invention, treating a patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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.

[0351] 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.

[0352] 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.

[0353] 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.

[0354] Improvement in one or more aspects of BD also leads to an overall improvement. Preferably, the treatment leads to remission.

[0355] 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.

[0356] 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.

[0361] 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.

[0362] 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.

[0363] 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.

[0364] 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).

[0365] 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.

[0366] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0367] Furthermore, antidepressants have been reported to induce isolated hypomanic events 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.

[0368] 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).

[0369] Therefore, when treated according to the present invention, patients do not experience treatment-emergent mania or hypomania.

[0370] 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.

[0371] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is administration by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in one breath.

[0372] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration preparation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0373] Buccal or sublingual administration can also be by a pharma- ceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in a formulation as is commonly known in the art (e.g., tablets, films, sprays, creams).

[0374] The administration is particularly by inhalation of an aerosol. Such an aerosol comprises (a) a pharma- ceutically acceptable gas and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, in particular about 2 mg / l to about 9 mg / l). The pharma- ceutical acceptable gas is preferably air.

[0375] The aerosol particles preferably contain less than 1 wt% impurities, in particular less than 0.5 wt% impurities. The aerosol particles further preferably contain less than 0.5 wt% 5-MeO-DMT decomposition products, in particular less than 0.2 wt% 5-MeO-DMT decomposition products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0376] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0377] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0378] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0379] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to generate aerosol particles. The thickness of the thin layer can be less than about 10 μm, particularly less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

[0380] A thin layer of 5-MeO-DMT configured on a solid support can be exposed to thermal energy via air passing over the thin layer. Alternatively, a thin layer of 5-MeO-DMT configured on a solid support can be exposed to thermal energy via the solid support.

[0381] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a flow rate of about 12 l / min for about 15 seconds.

[0382] The aerosol particles can be contained in a volume of about 3 liters or less, particularly a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0383] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharma-ceutically acceptable salt thereof are provided in the form of an aerosol. Such an aerosol has a suitable aerosol particle mass concentration so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0384] The aerosol useful in the present invention can be formed using thermal energy.When using thermal energy to form aerosol of a compound, it is very difficult to predict the conditions suitable for safe, efficient and predictable aerosolization, especially when the aerosol is to be used to deliver the compound to a patient systemically via the lungs.Relevant variables in this context include a) the dose of the compound, b) the morphological state of the compound that is made aerosolizable (e.g., crystalline form, or thin layer form), c) the amount of thermal energy that the compound is exposed to (defined by temperature and duration of exposure), and d) the volume of air that is introduced to create the aerosol (defined by flow rate and duration of airflow).

[0385] The compositions and methods described herein are for the safe, efficient and predictable systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized, preferably nearly completely or completely, to a defined extent, that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., within one deep breath), and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0386] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

[0387] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT configured on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0388] The generation of aerosol particles characterized by an aerodynamic mass median diameter of less than 3 microns, containing less than 1% wt of impurities and less than 0.5% wt of 5-MeO-DMT degradation product drug in the aerosol volume, and capable of being delivered to a patient via a single inhalation, is achieved by defining a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by air flow rate and duration of air flow).

[0389] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, where the air is heated. The temperature of the heated air passing over the thin layer may range from about 180° C. to about 260° C. The temperature of the air passing over the thin layer may in particular be about 210° C.

[0390] Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180°C to about 420°C.

[0391] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, being at least 99%, preferably at least 99.5% pure.

[0392] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Specific preferred amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0393] The solid support on which 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided may have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders less than 1.0 mm in diameter, boxes less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a large surface area to volume ratio (e.g., greater than 100 per meter) and a large surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0394] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface area to volume ratio of about 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (about 400 per meter).

[0395] A number of different materials are used to construct the solid support. Such material types include, but are not limited to, metals, inorganic materials, carbon-containing materials, and polymers. Examples of material types are: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0396] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m 2 1 / g alumina (Aldrich, St. Louis, Mo.) and silicon wafers such as those used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0397] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, in particular less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, in particular in the range of 0.3 μm to 7.5 μm.

[0398] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined at a flow rate between about 6 liters per minute and about 40 liters per minute, preferably between about 8 liters per minute and about 16 liters per minute, and the duration of the air flow is selected so that the total volume of the aerosol does not exceed about 3 liters, and the total volume of the aerosol is preferably between about 1 liter and 3 liters (such as between 2 liters and 3 liters). For example, at an air flow rate of about 6 liters per minute, the duration of the air flow should be less than about 30 seconds. A specific effective air flow rate and duration of the air flow is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective air flow rate and duration of the air flow is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective air flow rate and duration of the air flow is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0399] The aerosol generation rate is greater than 0.1 mg / sec.

[0400] The aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l).

[0401] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0402] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT decomposition products, preferably less than 0.2% wt of 5-MeO-DMT decomposition products.

[0403] A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT configured on a solid support as a thin layer less than 5 microns thick to a temperature of 210° C. for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt of 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0404] Those skilled in the art who are aware of the aerosol characteristics and aerosolization conditions defined in the present invention can identify suitable vaporization devices or systems that lead to the required aerosol characteristics.Examples of such suitable vaporization devices or systems include, for example, the Volcano Medic Vaporization System (Storz & Bickel, Germany, as disclosed in, for example, EP 0 933 093 B1, and EP 1 884 254 B1, and registered Community design 003387299-0001), which includes a dosage capsule with associated drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA, as disclosed in, for example, US 7,458,374 B2, US 9,370,629 B2, and US 9,687,487 B2).The generated aerosol is collected in a balloon, from which it can be inhaled by the patient.

[0405] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (dosing schemes).

[0406] 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.

[0407] Thus, achieving a peak experience more rapidly, in a greater percentage of patients, and with greater reproducibility within an individual patient compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0408] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., no attenuation or disappearance of the hallucinogenic effect after re-administration) as the basis for enabling a dosing regimen with frequent re-administration (e.g., more than once a day or daily) designed to increase the incidence of peak experiences and thereby increase the therapeutic effect. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time point), induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur with a higher dose, thereby affecting the experience in a positive way. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance at the patient population level.

[0409] 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.

[0410] 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).

[0411] The dosage of 5-MeO-DMT administered to 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) ranges from about 1 mg to about 25 mg, or any amount within that range, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharma- ceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. It should be noted that when a range is given herein, such as "from about 1 mg to about 25 mg," the inventors contemplate all discrete values ​​within that range, some of which are specifically recited, but not all of which are recited (solely for the sake of brevity).

[0412] 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.

[0413] 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 comprises sustaining a clinical response, including a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0414] 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.

[0415] 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.

[0416] 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.

[0417] 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, the interval between each dose within each treatment block being about 1-4 hours, preferably 1-2 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.

[0418] 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 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0419] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0420] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0421] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increment is 6 mg, the dosage of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage of the third administration will be 18 mg.

[0422] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration and to a dosage selected from about 14 mg to about 20 mg for the third administration, 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. Specific amounts that are effective for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0423] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 20 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines 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. For example, if a patient experienced a hallucinogenic high experience at a dose of 18 mg, and therefore the highest dosage in the first treatment block was 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0424] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, then increased to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dosage selected from about 14 mg to about 20 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 6 mg, about 12 mg, and about 18 mg.

[0425] It is understood that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0426] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0427] The occurrence of a "hallucinatory peak experience" in a patient can be identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0428] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0429] In accordance with the present invention, the occurrence of a "hallucinatory 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 referred to as 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?

[0430] Aspects of the invention 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.

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] 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.

[0436] 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.

[0437] 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.

[0438] 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.

[0439] 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.

[0440] 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.

[0441] 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 4 mg to about 20 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma-ceutical acceptable salt is administered instead of 5-MeO-DMT.

[0442] 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 6 mg, or about 12 mg, or about 18 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0443] 14. 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.

[0444] 15. 5-MeO-DMT or a pharma- ceutical or pharmaceutical acceptable salt thereof for use according to any one of aspects 1 to 14, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 8 mg for a first administration, then increased to a dosage of about 8 mg to about 14 mg for a second administration, unless the patient has yet experienced a hallucinogenic climax experience, and then increased to a dosage of about 14 mg to about 20 mg for a third administration, unless the patient has yet experienced a hallucinogenic climax experience; or, wherein an equimolar amount of the pharma-ceutical or pharmaceutical acceptable salt is administered in place of 5-MeO-DMT.

[0445] 16. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 15, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0446] 17. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 14 to 16, 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.

[0447] 18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 11 to 17, wherein the onset of a hallucinogenic peak experience is identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0448] 19. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 18, wherein the onset of a hallucinogenic climax experience is identified by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0449] 20. 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 by inhalation, or by nasal, buccal or sublingual administration.

[0450] 21. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 20, wherein the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered in the form of an aerosol, said aerosol comprising (a) a pharma- ceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and wherein the aerosol particle mass concentration of the aerosol is from about 0.5 mg / l to about 18 mg / l, for example from about 0.5 mg / l to about 12.5 mg / l.

[0451] 22. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 21, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof constituted on a solid support to thermal energy, and b) passing air over the thin layer to generate aerosol particles.

[0452] 23. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 20 to 22, wherein the dosage of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof to be administered to the patient is inhaled in one breath.

[0453] 24. 5-MeO-DMT for use according to embodiments 20 to 23, wherein the 5-MeO-DMT is used in the form of a free base.

[0454] 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 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.

[0455] 26. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 25, 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.

[0456] 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 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0457] 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0458] 29. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 28, 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.

[0459] 30. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 29, 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.

[0460] 31. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 30, 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.

[0461] 32. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 31, 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.

[0462] 33. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 32, 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.

[0463] 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 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 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0464] 35. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 34, 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.

[0465] 36. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 35, 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.

[0466] 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 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.

[0467] 38. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 37, 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.

[0468] 39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 38, 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.

[0469] 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 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 following the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0470] 41. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 40, 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.

[0471] 42. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 41, 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.

[0472] 43. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 42, wherein said patient does not experience treatment-emergent mania or hypomania.

[0473] 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0474] 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0475] 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0476] 47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0477] 48. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 47, 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.

[0478] 49. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 48, wherein said treatment improves at least one of sleep disorders, psychomotor developmental delay, negative thinking, anxiety, cognitive impairment, and social / emotional withdrawal or isolation.

[0479] 50. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 49, wherein the patient suffers from a sleep disorder and the treatment reduces or eliminates the sleep disorder.

[0480] 51. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, wherein the patient suffers from insomnia and the treatment reduces or eliminates the insomnia.

[0481] 52. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, wherein the patient suffers from hypersomnia and the treatment reduces or eliminates the hypersomnia.

[0482] 53. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 50 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0483] 54. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 50 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0484] 55. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 50 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0485] 56. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 50 to 55, 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.

[0486] 57. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, 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.

[0487] 58. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 57, 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.

[0488] 59. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 57, 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.

[0489] 60. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 57, 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.

[0490] 61. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 50, 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0491] 62. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 50 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0492] 63. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, 61 or 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0493] 64. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 50 or 61 to 63, 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.

[0494] 65. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 50, 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 occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0495] 66. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 65, 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.

[0496] 67. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 65, 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.

[0497] 68. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 65, 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.

[0498] 69. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, 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.

[0499] 70. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0500] 71. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50, 69 or 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0501] 72. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 50 or 69 to 71, 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.

[0502] 73. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 49, 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.

[0503] 74. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 73, 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.

[0504] 75. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 73, 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.

[0505] 76. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 73, 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.

[0506] 77. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 49, 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.

[0507] 78. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 49 or 77, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder is reflected 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.

[0508] 79. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 49, 77 or 78, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder is reflected 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.

[0509] 80. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 49 or 77 to 79, wherein the patient suffers from a sleep disorder, and the reduction or elimination of the sleep disorder is reflected 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.

[0510] 81. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 50, wherein the patient suffers from a sleep disorder, and wherein a 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.

[0511] 82. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 81, 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.

[0512] 83. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 81, 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.

[0513] 84. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 81, 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 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 until the time of evaluation.

[0514] 85. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 84, wherein the patient suffers from psychomotor developmental retardation and the treatment reduces or eliminates the psychomotor developmental retardation.

[0515] 86. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, wherein said treatment ameliorates or eliminates reduced energy and activity and / or reduced motivation.

[0516] 87. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85 or 86, wherein the reduction or elimination of said psychomotor developmental delay is reflected by at least an improvement in said 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.

[0517] 88. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 85 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 at the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0518] 89. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 85 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0519] 90. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 85 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0520] 91. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 85 to 90, 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.

[0521] 92. 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 85 or 86, 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, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0522] 93. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 92, 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.

[0523] 94. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 92, 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.

[0524] 95. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 92, 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.

[0525] 96. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS inhibition item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0526] 97. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 85 or 96, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS inhibition 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.

[0527] 98. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, 96 or 97, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS inhibition item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0528] 99. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85 or 96 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 inhibition item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0529] 100. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, or 96 to 99, wherein the reduction or elimination of the psychomotor developmental delay is reflected by at least an improvement in the score on the MADRS inhibition item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0530] 101. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 85, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS inhibition item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0531] 102. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 101, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS inhibition item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0532] 103. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 101, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS inhibition item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0533] 104. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 101, wherein the reduction or elimination of the psychomotor developmental delay as reflected by an improvement in the score on the MADRS inhibition item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0534] 105. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, 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.

[0535] 106. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0536] 107. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85, 105 or 106, 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.

[0537] 108. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85 or 105 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0538] 109. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 85 or 105 to 108, 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.

[0539] 110. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 84, 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.

[0540] 111. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 110, 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.

[0541] 112. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 110, 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.

[0542] 113. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 110, 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.

[0543] 114. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 113, wherein the patient is suffering from negative thoughts and the treatment reduces or eliminates the negative thoughts.

[0544] 115. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, wherein said treatment reduces or eliminates feelings of worthlessness, feelings of helplessness and despair, and / or feelings of guilt.

[0545] 116. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 114 or 115, 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0546] 117. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114 to 116, 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.

[0547] 118. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0548] 119. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0549] 120. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114 to 119, 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.

[0550] 121. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114 or 115, 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.

[0551] 122. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 121, 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.

[0552] 123. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 121, 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.

[0553] 124. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 121, 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.

[0554] 125. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 114 or 115, wherein the reduction or elimination of said negative thinking is reflected by at least an improvement in said 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.

[0555] 126. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, 115 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0556] 127. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, 115, 125 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0557] 128. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 114, 115 or 125 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0558] 129. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 114, 115 or 125 to 128, 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.

[0559] 130. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114 or 115, 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.

[0560] 131. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 130, 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.

[0561] 132. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 130, 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.

[0562] 133. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 130, 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.

[0563] 134. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 114 or 115, wherein the reduction or elimination of said negative thoughts is reflected by at least an improvement in said score on the BPRS guilt item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0564] 135. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, 115 or 134, wherein the reduction or elimination of negative thoughts is reflected by an improvement in the score on the BPRS guilt 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.

[0565] 136. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 114, 115, 134 or 135, 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.

[0566] 137. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 114, 115 or 134 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0567] 138. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 114, 115 or 134 to 137, 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.

[0568] 139. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114 or 115, 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.

[0569] 140. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 139, 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.

[0570] 141. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 139, 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.

[0571] 142. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 139, 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.

[0572] 143. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114 or 115, 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0573] 144. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, 115 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0574] 145. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 114, 115, 143 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0575] 146. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114, 115 or 143 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0576] 147. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 114, 115 or 143 to 146, 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.

[0577] 148. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 113, 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.

[0578] 149. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 148, 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.

[0579] 150. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 148, 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.

[0580] 151. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 148, 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.

[0581] 152. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 151, wherein the patient suffers from anxiety and the treatment reduces or eliminates the anxiety.

[0582] 153. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, wherein the 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.

[0583] 154. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 152 or 153, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BDRS anxiety 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.

[0584] 155. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 152 to 154, 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.

[0585] 156. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 152 to 155, 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.

[0586] 157. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 152 to 156, 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.

[0587] 158. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, 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.

[0588] 159. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 158, 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.

[0589] 160. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 158, 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.

[0590] 161. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 158, 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.

[0591] 162. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, wherein the reduction or elimination of anxiety is reflected by at least an improvement in the score on the BPRS anxiety item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0592] 163. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 152 or 162, 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, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0593] 164. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, 162 or 163, 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.

[0594] 165. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 152 or 162 to 164, 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.

[0595] 166. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 152 or 162 to 165, 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.

[0596] 167. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, 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.

[0597] 168. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 167, 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.

[0598] 169. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 167, 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.

[0599] 170. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 167, 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.

[0600] 171. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, 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.

[0601] 172. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0602] 173. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152, 171 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0603] 174. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152 or 171 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0604] 175. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 152 or 171 to 174, 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.

[0605] 176. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 151, 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.

[0606] 177. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 176, 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.

[0607] 178. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 176, 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.

[0608] 179. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 176, 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.

[0609] 180. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 179, wherein the patient is suffering from cognitive impairment and the treatment reduces or eliminates the cognitive impairment.

[0610] 181. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0611] 182. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 180 or 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 at least one day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0612] 183. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 180 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0613] 184. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 180 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0614] 185. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 180 to 184, 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.

[0615] 186. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180, 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.

[0616] 187. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 186, 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.

[0617] 188. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 186, 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.

[0618] 189. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 186, 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.

[0619] 190. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 180, 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0620] 191. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 180 or 190, wherein the reduction or elimination of the cognitive impairment is reflected by at least an improvement in the score on the MADRS concentration difficulties 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.

[0621] 192. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180, 190 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0622] 193. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 180 or 190 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0623] 194. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 180 or 190 to 193, 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.

[0624] 195. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180, 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.

[0625] 196. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 195, 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.

[0626] 197. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 195, 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.

[0627] 198. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 195, 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.

[0628] 199. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180, 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.

[0629] 200. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0630] 201. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180, 199 or 200, wherein the patient suffers 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.

[0631] 202. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180 or 199 to 201, wherein the patient suffers 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.

[0632] 203. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 180 or 199 to 202, wherein the patient suffers 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.

[0633] 204. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 179, wherein the patient is suffering from cognitive impairment, and 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.

[0634] 205. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 204, 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.

[0635] 206. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 204, 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.

[0636] 207. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 204, 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.

[0637] 208. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 207, wherein the patient suffers from social / emotional withdrawal or isolation, and the treatment reduces or eliminates the social / emotional withdrawal or isolation.

[0638] 209. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208, wherein said treatment reduces or eliminates at least one of anhedonia, emotional withdrawal and affective flattening.

[0639] 210. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208 or 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0640] 211. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208 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 at least 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0641] 212. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0642] 213. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0643] 214. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208 to 213, 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.

[0644] 215. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208 or 209, 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.

[0645] 216. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 215, 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.

[0646] 217. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 215, 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0647] 218. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 215, 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.

[0648] 219. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208 or 209, 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 inability to have feelings item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0649] 220. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 or 219, 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 Have Emotions 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.

[0650] 221. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208, 209, 219 or 220, 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0651] 222. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 219-221, 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 Inability to Have Emotions item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0652] 223. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 219-222, 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.

[0653] 224. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208 or 209, 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.

[0654] 225. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 224, 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.

[0655] 226. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 224, 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.

[0656] 227. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 224, 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 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0657] 228. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208 or 209, wherein the reduction or elimination of said social / emotional withdrawal or detachment is reflected by at least an improvement in said 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.

[0658] 229. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 or 228, 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.

[0659] 230. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209, 228 or 229, 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0660] 231. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 228-230, 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0661] 232. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 228 to 231, 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.

[0662] 233. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208 or 209, 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.

[0663] 234. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 233, 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.

[0664] 235. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 233, 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.

[0665] 236. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 233, 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.

[0666] 237. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208 or 209, 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 Affective Flattening item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0667] 238. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 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 flattened BPRS affect 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.

[0668] 239. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 208, 209, 237 or 238, wherein the reduction or elimination of the social / emotional withdrawal or detachment is reflected at least by an improvement in the score on the BPRS Affective Flattening item 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0669] 240. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 237-239, 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 Affective Flattening item 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0670] 241. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 208, 209 or 237 to 240, 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 Affective Flattening item 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0671] 242. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208 or 209, wherein the reduction or elimination of the social / emotional withdrawal or detachment, as reflected by an improvement in the score on the BPRS Affect Flattening item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0672] 243. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 242, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Affective Flattening item persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0673] 244. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 242, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Affective Flattening item persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0674] 245. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 242, wherein the reduction or elimination of the social / emotional withdrawal or detachment as reflected by an improvement in the score on the BPRS Affective Flattening item persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0675] 246. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208 or 209, 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.

[0676] 247. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0677] 248. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209, 246 or 247, wherein the patient suffers from social / emotional withdrawal or detachment, and improvement of social / emotional withdrawal or detachment 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.

[0678] 249. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 or 246 to 248, 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0679] 250. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 208, 209 or 246 to 249, 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 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0680] 251. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 207, wherein the patient suffers from social / emotional withdrawal or detachment, and 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.

[0681] 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 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.

[0682] 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 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.

[0683] 254. 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 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.

[0684] 255. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 254, wherein said treatment reduces or eliminates suicidal thoughts.

[0685] 256. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 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 about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0686] 257. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255 or 256, 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.

[0687] 258. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 255 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0688] 259. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 255 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0689] 260. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 255 to 259, 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.

[0690] 261. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255, 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.

[0691] 262. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 261, 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.

[0692] 263. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 261, 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.

[0693] 264. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 261, 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.

[0694] 265. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 255, wherein the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score on the MADRS suicidal thoughts item about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0695] 266. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 255 or 265, 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.

[0696] 267. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255, 265 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0697] 268. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 255 or 265 to 267, wherein the reduction or elimination of suicidal ideation is reflected at least by 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.

[0698] 269. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 255 or 265 to 268, 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.

[0699] 270. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255, 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.

[0700] 271. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 270, 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.

[0701] 272. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 270, 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.

[0702] 273. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 270, 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.

[0703] 274. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255, 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.

[0704] 275. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255 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 on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0705] 276. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255, 274 or 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 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0706] 277. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255 or 274 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0707] 278. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 255 or 274 to 277, 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.

[0708] 279. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 254, 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.

[0709] 280. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 279, 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.

[0710] 281. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 279, 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.

[0711] 282. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 279, 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.

[0712] 283. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 282, wherein said treatment reduces or eliminates at least one of psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation. EXAMPLES

[0713] 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.

[0714] Example 1 – Generation and administration of 5-MeO-DMT aerosol Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask such that the target dose of 5-MeO-DMT free base to be administered to a subject or patient by inhalation is contained in a solution volume of 200 μl. A typical target dose of 5-MeO-DMT is 1 mg to 25 mg. For example, if the target dose of 5-MeO-DMT is 18 mg, then 90 mg of 5-MeO-DMT would be dissolved in 100% ethanol to a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until the time of use.

[0715] Step 2: 200 μl of the solution is transferred into a dosing capsule containing a drip pad (Storz & Bickel, Germany) and the dosing capsule is then closed with its lid.

[0716] 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, which has been preheated with the temperature set to 55°C. The vaporizer airflow is then turned on for 60 seconds at a pre-set flow rate of approximately 12 l / min. The heated air flows into the dosing capsule, evaporating the ethanol and leaving the target dose of 5-MeO-DMT in the capsule as a thin layer covering the stainless steel wire mesh. It can be confirmed that the dosing capsule has been correctly prepared by demonstrating that the final weight increase of the capsule compared to the weight of the empty capsule is approximately equal to the target dose of 5-MeO-DMT.

[0717] Step 4: The prepared dose capsule is removed from the filling chamber. The dose capsule is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which is preheated by setting the temperature at 210° C. and has the airflow turned on for at least 5 minutes and turned off immediately before transferring the capsule. A valved inhalation balloon (Storz & Bickel, Germany) is attached to the socket of the filling chamber, the filling chamber is tightly closed, and immediately thereafter the airflow is turned on for exactly 15 seconds at a pre-set 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 weight of the capsule has returned approximately to its initial weight.

[0718] 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 to the subject or patient.

[0719] Step 6: To prepare for administration, ask the patient to first inhale deeply and exhale completely 1-2 times, concluding this sequence with a deep exhale. 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, then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0720] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850 A1, the contents of which are incorporated herein by reference.

[0721] Example 2 – Preparation of high purity 5-MeO-DMT 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 vol) at 35-40° 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. After stirring at 7-12° C. for 10 min, crystallization occurred. Following stirring at 7-12° C. for 1 h, the batch was filtered. After washing with MTBE (1 mL, 0.5 vol), the batch was dried under vacuum at 7-12° C. for 3.5 h to give 1.02 g (50% recovery) of a pale orange solid. The isolated solid was analyzed for purity by HPLC as described in WO 2020 / 169850 A1. The purity was found to be 99.74% area.

[0722] Analysis further indicates that the levels of individual impurities were below 0.10% area. Solvent analysis of the sample indicated an MTBE level of 17 ppm.

[0723] Example 3 – Preparation of 5-MeO-DMT hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0724] The free base of 5-MeO-DMT was mixed 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.

[0725] 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 in vacuum at 40° C. for 18 hours.

[0726] An off-white crystalline material was obtained.

[0727] The salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern including peaks at 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, 24.8°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ measured using Cu Kα radiation.

[0728] Example 4 – Determination of inhibition constants for 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.

[0729] 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.

[0730] 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 kept 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 to 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.

[0731] 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 WAY 100635 (non-specific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0732] 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 μM WAY 100635 (non-specific binding) or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10000 nM.

[0733] 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 rapidly washed with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity was measured by liquid scintillation counting (1 ml Packard MV Gold scintillator).

[0734] The compound concentration required to inhibit 50% of the specific binding (IC 50 ) and Hill Slope were calculated by using nonlinear regression. i was calculated using a one-site binding model that takes into account ligand depletion.

[0735] 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 cellular debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice and the pellet was homogenized again 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 twice more (20,500 x g, 10 min) to wash the tissue. The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer (pH 7.4) to a tissue concentration equivalent to 10 mg wet weight tissue / ml. All centrifugations were performed at 4°C.

[0736] 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 μM ketanserin (nonspecific binding) for 60 min at 25° C. Assay buffer and wash buffer consisted of 50 mM Tris-HCl buffer (pH 7.4).

[0737] For the displacement assay, frontal cortex 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 μM ketanserin (non-specific binding), or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10,000 nM.

[0738] Membrane-bound radioactivity was collected and measured as above, and data analysis was also performed as above.

[0739] result In hippocampal membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.51, 0.28 and 0.52 nM, respectively.

[0740] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0741] In frontal cortical membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.11, 0.08 and 0.08 nM, respectively.

[0742] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0743] 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.

[0744] 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, has been completed in patients with treatment-resistant major depressive disorder (TRD). 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 escalating doses of 5-MeO-DMT. Patients (n=8) received at least one and up to three doses of 5-MeO-DMT daily (6 mg, 12 mg, and 18 mg), with higher doses administered only if the peak experience was not achieved with the previous 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.

[0745] In Part A, 3 of 4 patients in both arms (12 mg and 18 mg) experienced at least one ADR. All of them were mild and resolved spontaneously. No SAEs were reported.

[0746] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission at post-dose day 7, and one additional patient (25%) in the 18 mg group had a MADRS clinical response at post-dose day 7. 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.

[0747] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0748] 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%).

[0749] 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.

[0750] The results are summarized in the table below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0751] Example 6 – Pharmacokinetic evaluation of 5-MeO-DMT and bufotenine To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups (8 subjects per group) were formed. Subjects received a single dose of 6 mg, 12 mg, or 18 mg of 5-MeO-DMT by inhalation. Blood samples were collected at 1, 2, 4, 7, 10, 15, 20, 30, and 45 minutes and at 1, 1.5, 2, 3, and 4 hours after administration.

[0752] 5-MeO-DMT concentrations were measured using LC-MS / MS. PK parameters were generated by algebraic analysis of individual concentration versus time plots. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0753] 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).

[0754] Table 3 below shows the median plasma concentration percentages of Cmax measured at the indicated time points. [Table 7]

[0755] Pharmacokinetic measurements were also performed using a dosing scheme based on ascending dose titration, with substantially similar results.

[0756] The plasma concentration of the 5-MeO-DMT metabolite bufotenine was also measured. In only a few samples were concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). From 15 min onwards, bufotenine concentrations were always below the LLOQ.

[0757] Substantially similar observations were made when subjects undergoing an escalating titration scheme were included.

[0758] Example 7 – Toxicity testing of 5-MeO-DMT 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101) under conditions that 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).

[0759] 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).

[0760] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0761] More specifically, on day 0, patients will receive up to three doses of 5-MeO-DMT: 6 mg, 12 mg, and 18 mg. 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 ≥ 75) after 6 mg administration; 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 clinically significant, as determined by the investigator. 3. Similarly, the third dose (18 mg) is administered only if: a. No peak experience (total score ≥ 75) was achieved 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 clinically significant, as determined by the investigator.

[0762] Patients will be assessed post-injection for hallucinatory peak experiences (based on a patient-rated visual analog scale, the PE scale), sedation, and other endpoints. Follow-up visits will be scheduled 1 and 7 days after the date of injecting.

[0763] All patients considered for participation in a clinical trial must meet the following criteria: 1. Females aged 18-45 years (inclusive) at the time of screening. 2. Body mass index (BMI) at screening: 18.5-35 kg / m 2 The range is inclusive. 3. Meets the PPD testing criteria as assessed by a testing psychiatrist or licensed psychologist: a. Diagnosis of major depressive disorder without psychotic features as determined by the Mini-Institute for Mental Illnesses (MINI) with perinatal onset occurring during pregnancy or later and within the first 4 weeks after delivery. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose 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. Must agree to total abstinence (abstain completely from heterosexual intercourse) or use a medically accepted method of contraception that is highly effective (failure rate <1%) 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 7 days after the end of the study and agree to keep any psychotherapy unchanged during the study.

[0764] Potential patients meeting 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 diagnosis of 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, in the opinion of the study investigator, renders the patient 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 for suicide as determined by a study psychiatrist or licensed psychologist based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS). 4. Receiving antidepressant therapy 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. Have previously experienced a significant adverse reaction to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the study investigator. Known allergy or hyper...

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, The aforementioned bipolar disorder is bipolar type II disorder. A pharmaceutical composition in which the patient is currently experiencing a major depressive episode.

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 patient has a total score of 19 or higher on the Bipolar Depression Rating Scale (BDRS) prior to treatment, for example, 24 or higher prior to treatment, and particularly 37 or higher prior to treatment.

4. The pharmaceutical composition according to claim 1, wherein the patient did not show sufficient improvement after at least two appropriate courses of drug therapy.

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, wherein the bipolar II disorder is a treatment-resistant type of bipolar II disorder.

7. The pharmaceutical composition according to claim 6, wherein a dose of approximately 4 mg to approximately 20 mg of 5-MeO-DMT is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered.

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

9. 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.

10. The pharmaceutical composition according to claim 9, wherein each subsequent dose after the first dose is administered in a larger dose than the previous dose.

11. The pharmaceutical composition according to claim 10, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in a dose of about 2 mg to about 8 mg for a first dose, then in an increased dose of about 8 mg to about 14 mg for a second dose, and then in an increased dose of about 14 mg to about 20 mg for a third dose.

12. The pharmaceutical composition according to claim 11, wherein the first dose of 5-MeO-DMT or an equimolar amount of the pharmaceutically acceptable salt is about 6 mg, the second dose of 5-MeO-DMT or an equimolar amount of the pharmaceutically acceptable salt is about 12 mg, and the third dose of 5-MeO-DMT or an equimolar amount of the pharmaceutically acceptable salt is about 18 mg.

13. The pharmaceutical composition according to claim 12, wherein the interval between two administrations is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably 1 to 2 hours.

14. The pharmaceutical composition according to claim 10, wherein the patient receives a subsequent dose unless the patient has experienced a hallucinogenic euphoric state.

15. The manifestation of the hallucinogenic peak experience is identified by achieving at least 60% of the maximum score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (mystical, positive mood, transcendence of time and space, and inexpressibility), or by achieving at least 60% of the maximum score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving at least 75 in the Peak Experience Scale (PES) Total Score, according to claim 14.

16. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by inhalation, or by nasal administration, buccal administration, or sublingual administration.

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

18. The pharmaceutical composition according to claim 17, wherein a clinical response, reflected by an improvement of at least 50% in the BDRS score or the MADRS score compared to the respective scores before treatment, is observed approximately 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

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

21. 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.

22. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered to the patient in a dose or administration schedule sufficient to induce a hallucinogenic peak experience.