5-Methoxy-N,N-dimethyltryptamine for the treatment of social / emotional withdrawal or isolation

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat patients suffering from social / emotional withdrawal or estrangement.

Description

[Technical Field]

[0001] The present invention relates to social / emotional withdrawal or detachment, particularly in relation to mental or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depression, anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, e.g., chronic pain and fibromyalgia; psychoactive substance use disorders. The present invention relates to improved methods for the treatment of social / emotional withdrawal or estrangement in patients suffering from mental and behavioral disorders, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0002] Social / emotional withdrawal or isolation can also occur in patients suffering from sleep disorders, such as insomnia.

[0003] Social / emotional withdrawal or estrangement can also occur in patients suffering from medical health conditions that lead to associated mental or neurological conditions, including traumatic brain injury (TBI).

[0004] Treatment involves administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. [Background technology]

[0005] Symptoms such as anhedonia, emotional withdrawal, and flat affect are collectively referred to herein as social / emotional withdrawal or isolation. Decreased social engagement is a further aspect associated with social / emotional withdrawal or isolation.

[0006] Anhedonia is the inability to experience pleasure. A patient suffers from anhedonia when there is a subjectively reduced ability to experience pleasure in usual activities. Anhedonia consists of a consummatory (or appetitive) component and an anticipatory (or appetitive) component. Consummatory pleasure refers to the "in-the-moment" pleasure experienced by a subject directly engaged in a pleasurable activity, while anticipatory pleasure refers to the experience of pleasure associated with a future activity.

[0007] Emotional withdrawal or detachment is the inability or unwillingness to connect with others on an emotional level.

[0008] Affective flattening is characterized by a subjective feeling of a decreased intensity or range of emotions and feelings.

[0009] Decreased social engagement is characterized by subjective reports of decreased social and interpersonal involvement or interaction.

[0010] Social / emotional withdrawal or isolation can have a significant impact on quality of life as well as lead to a variety of secondary health problems.

[0011] Thus, there is a need for improved methods for the treatment of social / emotional withdrawal or estrangement, particularly social / emotional withdrawal or estrangement associated with psychiatric or neurological disorders. Summary of the Invention

[0012] It is an object of the present invention to provide improved therapies that are more effective than previously described therapies (i.e., a) a greater percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a more rapid onset of clinical response, and / or d) a more durable clinical response).

[0013] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies 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 specific subgroups of disease conditions that would benefit from such improved psychoactive therapies.

[0014] The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from social / emotional withdrawal or detachment, particularly symptoms such as anhedonia, emotional withdrawal, flat affect, and / or decreased social engagement.

[0015] The present invention relates to social / emotional withdrawal or detachment, particularly in relation to mental or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depression, anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, e.g., chronic pain and fibromyalgia; psychoactive substance use disorders. The present invention provides improved methods for the treatment of social / emotional withdrawal or isolation in patients suffering from mental and behavioral disorders, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0016] The present invention also provides improved methods for treating social / emotional withdrawal or isolation in patients suffering from sleep disorders, such as insomnia.

[0017] The present invention also provides improved methods for treating social / emotional withdrawal or alienation in patients suffering from medical conditions leading to related psychiatric or neurological conditions, including traumatic brain injury (TBI).

[0018] The present invention also provides dose ranges and administration regimens useful for treating social / emotional withdrawal or distancing, particularly anhedonia, emotional withdrawal, flat affect and / or decreased social engagement. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition As 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 pharmaceutically 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 can be calculated from the weight of the free base, assuming an equimolar amount is used.

[0020] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional, in accordance with accepted medical practice, as suffering from social / emotional withdrawal or distancing, or who has been diagnosed by a licensed professional, in accordance with accepted medical practice, as having a psychiatric or neurological disorder associated with social / emotional withdrawal or distancing, in which case assessment of social / emotional withdrawal or distancing may or may not be part of the diagnosis.

[0021] Diagnosis of mental or nervous system disorders can be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. As will be apparent from the discussion of specific conditions below, in some cases, the criteria can be modified or supplemented to better define patients or patient groups that will particularly benefit from the treatment of the present invention. In any case, the diagnosis is made by a doctor or psychologist. It is not sufficient for the human subject himself to believe that he is suffering from a disorder.

[0022] 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, and includes the administration of compounds and 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.

[0023] "Treatment of social / emotional withdrawal or isolation" is intended to include the management and care of a patient for the purpose of addressing social / emotional withdrawal or isolation, and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of, or eliminate, social / emotional withdrawal or isolation.

[0024] Social / emotional withdrawal or isolation may be associated with sleep disorders, such as insomnia, psychiatric or nervous system disorders, or other medical conditions.

[0025] Patient may suffer from treatment-resistant disease.Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy; for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses.At least two previous treatment courses are particularly administered during depressive episodes, for example, when patient suffers from a disorder characterized by depressive episodes, they are administered during depressive episodes.

[0026] As used in the context of the present invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is sought 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.

[0027] "Clinical response" includes, but is not limited to, improvements on rating scales assessing (i) social / emotional withdrawal or isolation or aspects of social / emotional withdrawal or isolation, and / or (ii) a psychiatric or neurological disorder or aspects of such a disorder, (iii) a medical condition leading to an associated psychiatric or neurological condition, and / or (iv) sleep.

[0028] The severity of the condition and changes in severity can be assessed by the Clinical Global Impression (CGI) scale, which is a measure of symptom severity, response to treatment, and effectiveness of treatment.

[0029] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the clinician's opinion (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0030] The CGI-Severity Scale (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 your 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 = patient with very severe illness.

[0031] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0032] 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 is achieved. Particularly preferred is a decrease in the CGI-S score of at least three grades and / or a score of 0 is achieved.

[0033] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, the clinician compares the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of project entry (before medication was started), this patient's condition has improved greatly since treatment began: 1 = very much; 2 = very much; 3 = very little; 4 = no change from baseline (before treatment began); 5 = very little; 6 = very little; 7 = very little since treatment began."

[0034] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is a companion scale to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0035] In addition to the individual items of the scales as described herein, sub-combinations of the individual items may also be used to assess specific disease aspects.

[0036] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a predetermined 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.

[0037] As used in the context of this invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosing regimen" (or "administration regimen") shall mean a defined sequence of one or more individual administrations.

[0038] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharmaceutically 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., (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample) / ((the amount of 5-MeO-DMT present in the sample) + (the sum of the amounts 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 pharmaceutically acceptable salt thereof) sample. The impurities may be contained in the starting material prior to aerosol formation, or the impurities may be decomposition products.

[0039] 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%.

[0040] The term "mass median aerodynamic diameter" (MMAD) refers to the calculated diameter where 50% of the particles present in the aerosol are larger and 50% are smaller than this diameter. The term "aerosol particle mass concentration" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the mass of aerosolized 5-MeO-DMT per unit time of aerosolization.

[0041] Social / emotional withdrawal or isolation Symptoms such as anhedonia, emotional withdrawal, and flat affect are collectively referred to herein as social / emotional withdrawal or isolation. Decreased social engagement is a further aspect associated with social / emotional withdrawal or isolation.

[0042] Anhedonia is the inability to experience pleasure. A patient does not suffer from anhedonia if there is no subjective decrease in the ability to experience pleasure from usual activities. Anhedonia is mild, when pleasure from usual pleasurable activities is slightly reduced; moderate, when pleasure from usual pleasurable activities is significantly reduced, with some pleasure from isolated activities maintained; or severe, when there is a complete inability to experience pleasure.

[0043] Anhedonia consists of a consummatory (or liking) component and an anticipatory (or wanting) component. Consummatory pleasure refers to the "in-the-moment" pleasure experienced by a subject directly engaged in a pleasurable activity, while anticipatory pleasure refers to the experience of pleasure associated with a future activity.

[0044] Affective flattening is characterized by a subjective sense of a decrease in the intensity or range of emotions and feelings. If there is no subjective sense of a decrease in the intensity or range of emotions and feelings, the subject does not exhibit affective flattening. Affective flattening is mild when the range of emotions is slightly constricted or the range or intensity of emotions is temporarily reduced; moderate when the range or intensity of emotions is significantly constricted, with some emotions being preserved, for example, an inability to cry; and severe when the range of emotions is significantly and completely constricted, or the subject is unable to experience normal emotions.

[0045] Emotional withdrawal or detachment is an inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item for emotional withdrawal, which is characterized as a patient's lack of ability to emotionally engage in the interview situation. According to the description of this BPRS item, emotional withdrawal is absent if a lack of emotional engagement is not indicated by spontaneously engaging with the interviewer most of the time, despite an occasional failure to return feedback, appearing distracted, or awkwardly smiling. A mild form of emotional withdrawal is indicated if a lack of emotional engagement is indicated by a noticeable failure to return feedback, appearing distracted, or lacking warmth, but responds to the interviewer when prompted. A moderate form of emotional withdrawal is present if emotional contact is absent for most of the interview because the subject does not respond in detail, is unable to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic traits. Furthermore, a moderately severe form of emotional withdrawal is present if emotional contact is absent for most of the interview. A severe form is when the subject actively avoids emotional engagement, or when the subject is frequently unresponsive, responds with yes / no, or responds with minimal emotion. A very severe form is when the subject consistently avoids emotional engagement, is unresponsive, responds with yes / no, walks away during the interview, or does not respond at all.

[0046] Reduced social engagement is characterized by subjective reports of decreased social and interpersonal involvement or interaction. If there is no report of decreased social and interpersonal involvement or interaction, social engagement is not decreased. Mild is when social engagement is slightly reduced and there is no impairment in social or interpersonal functioning; moderate is when social engagement is clearly reduced and there is some functional sequelae, e.g., avoidance of some social engagement or conversation; and severe is when social interaction is significantly reduced or almost all forms of social contact are avoided, e.g., refusing to answer the phone or meet with friends or family.

[0047] Social / emotional withdrawal or detachment may be associated with a psychiatric disorder, or a neurological disorder, or some other medical condition.

[0048] Mental or neurological disorders leading to or associated with social / emotional withdrawal or detachment include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), including bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depression, anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders. These include: mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0049] Social / emotional withdrawal or isolation can also occur in patients suffering from sleep disorders, such as insomnia.

[0050] Social / emotional withdrawal or estrangement can also occur in patients suffering from medical health conditions that lead to associated mental or neurological conditions, including traumatic brain injury (TBI).

[0051] Measuring social / emotional withdrawal or distancing Social / emotional withdrawal or distancing, or its individual aspects such as anhedonia, emotional withdrawal, and flat affect, can be assessed by a variety of means, such as questionnaires or scales.

[0052] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient has a specific mental or neurological disorder may include items related to social / emotional withdrawal or estrangement.

[0053] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale measuring anhedonia, or the inability to experience pleasure. Items encompass the domains of social interactions, food and drink, sensory experiences, and interests / pastime. A score of 2 or less defines a "normal" score, while an "abnormal" score is defined as 3 or greater. Each item has four response options: strongly disagree, disagree, agree, and strongly agree. Each "disagree" response is worth 1 point, and each "agree" response is worth 0 points. Thus, final scores range from 0 to 14. The SHAPS has adequate construct validity and adequate test-retest reliability. High internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression, but it is also frequently used to assess anhedonia in other patient populations.

[0054] In principle, SHAPS measures hedonic tone over the past few days using 14 hypothetical formulated items, although due to the hypothetical nature of the items, appropriate shorter recall periods can be applied for earlier assessments.

[0055] Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort, and pleasure of completion across four hedonic domains: hobbies, food / drink, social activities, and sensory experiences, can be used to assess anhedonia. It consists of 17 items assessing current anhedonia status. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much), with higher scores indicating less anhedonia. When all items are summed, the total score ranges from 0 to 68. Participants are asked to provide two or three examples of their favorite activities for each of the four hedonic domains: hobbies (4 items, total score 0–16), food / drink (4 items, total score 0–16), social activities (4 items, total score 0–16), and sensory experiences (5 items, total score 0–20).

[0056] The Personality Inventory for DSM-5 (PID-5)-Adult is a 220-item self-rated personality trait scale for adults aged 18 years and older. The test assesses 25 personality trait facets, including anhedonia, anxiety, attention-seeking, callousness, fakeness, depression, distractibility, eccentricity, emotional lability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, manipulativeness, perceived loss of control, obsessive attachment, limited emotionality, rigid perfectionism, risk-taking, separation anxiety, submissiveness, suspiciousness, unusual beliefs and experiences, and social withdrawal, with each trait facet consisting of 4 to 14 items.

[0057] The trait facet Anhedonia includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (reverse-scored items are marked with the letter "R"), the trait facet Withdrawal includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186, and the trait facet Intimacy Avoidance includes items 89, 97R, 108, 120, 145, and 203. Combining these three trait facets yields a broader trait domain termed "Avoidance."

[0058] This measure is completed by individuals before seeing a clinician. For each item, individuals are asked to rate how well the item generally describes them.

[0059] Each metric item is rated on a 4-point scale. Item response categories are: 0 = not true at all or not true most of the time; 1 = not true sometimes or not true very often; 2 = true sometimes or very often; and 3 = true very much or true most of the time. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, the items are reverse coded before calculating the scale score.

[0060] Scores for items within each trait facet should be summed and entered into the appropriate raw facet score box. Additionally, clinicians are asked to calculate and use a mean score for each facet and domain. Mean scores reduce the overall score and each domain score to a four-point scale, allowing clinicians to consider an individual's personality dysfunction relative to observed norms. The mean facet score is calculated by dividing the raw facet score by the number of items in the facet (e.g., if all items within the "anhedonia" facet are rated "sometimes or somewhat true," the mean facet score would be 16 / 8 = 2, indicating moderate anhedonia). The mean domain score is calculated by summing and averaging the three facet scores that primarily contribute to a specific domain. For example, if the mean facet scores for anhedonia, intimacy avoidance, and withdrawal (a measure primarily measuring estrangement) are all 2, these scores would sum to 6, resulting in a mean domain score of 6 / 3 = 2. Higher mean scores indicate greater dysfunction of specific personality trait facets or domains.

[0061] High scores on facets or domains may indicate areas of importance and problem for the individual receiving care that may warrant further evaluation, treatment, and follow-up.

[0062] Scales for assessing mental and nervous system disorders A number of scales have been proposed to assess the severity of psychiatric or neurological disorders, and these scales are based on tests that can be self-administered or administered by a clinician.

[0063] Scales that can be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring psychiatric or neurological disorders, which are discussed in more detail below.

[0064] Treatment outcomes are assessed using one or more indexes or scales at one or more time points after the end of the treatment course.

[0065] The assessment can be performed after the acute hallucinatory experience has subsided. A suitable time point for early assessment is generally about 2-3 hours after the last dose. Early assessment can typically be performed, for example, about 2 hours or about 3 hours after the last dose.

[0066] However, assessment of the effect on sleep disturbances can be performed as early as the day after treatment (ie, Day 1) to allow the treated patient an opportunity to get at least one night's sleep.

[0067] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. Evaluation will occur no earlier than 12 hours after the last dose, and in any event no later than overnight after the last dose and no later than 36 hours after the last dose. Evaluation can occur after approximately 24 hours.

[0068] Assessment on day 7 or assessment at day 7 refers to assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0069] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response, if the clinical response is evaluated at an early time point (for example, 2 hours) after drug administration based on the endpoint made during a longer recall period (for example, usually 7 days for MADRS), reasonable modification of such endpoint (for example, changing the MADRS recall period to 2 hours, and carrying forward the sleep items recorded at the baseline before drug administration) can be applied.The same applies to any other scales applied herein, unless the recall period is specifically indicated.

[0070] At this early point, the considerations outlined apply because, on the one hand, the influence of the patient's condition before treatment on any scores recorded after treatment to assess clinical response should be kept as low as possible, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0071] 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 a recall period adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0072] Resting networks and social / emotional withdrawal or isolation Brain processes can be studied by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0073] Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0074] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0075] Various resting-state networks have been identified and named primarily based on spatial similarities between resting-state networks and activity patterns seen in task-fMRI experiments.

[0076] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0077] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, including certain forms of social / emotional withdrawal or isolation, which are associated with modulation of functional connectivity between one or more regions within a specific resting-state network and / or one or more additional resting-state networks.

[0078] Anhedonia, an important aspect of social / emotional withdrawal or isolation, is associated with modulation of RSNs. More specifically, anhedonia is associated with hyperconnectivity of the visual network and expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia is also associated with decreased inter-network connectivity between the DMN network, salience network, DAN network, somatomotor network, and visual network.

[0079] Furthermore, emotional detachment in adult psychopathy is associated with structural abnormalities in the dorsal DMN. The dorsal DMN is of particular interest in the development of psychopathy due to its associated functions. Specifically, the dorsal DMN and the regions it connects to—the medial prefrontal cortex and posterior cingulate cortex (PCC)—underpin emotional, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are associated with the emotional and interpersonal differences that define the disorder.

[0080] Thus, patients suffering from social / emotional withdrawal or estrangement have altered functional connectivity within and / or between RSNs compared to age-matched healthy controls. Modulations are observed within and / or between the DMN, salience, DAN, somatomotor, and visual networks.

[0081] RSNs often associated with social / emotional withdrawal or detachment are associated with psychiatric or neurological disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depression; anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders; For example, chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0082] Resting-state networks involved in social / emotional withdrawal or distancing are also affected by mental or neurological conditions that are the result of certain medical health conditions, such as traumatic brain injury (TBI).

[0083] Resting-state networks involved in social / emotional withdrawal or distancing are also affected by sleep disorders, such as insomnia, and indeed, social / emotional withdrawal or distancing and sleep disturbances are correlated.

[0084] Treatment of social / emotional withdrawal or isolation and mental or nervous system disorders According to the present invention, social / emotional withdrawal or isolation that occurs in patients suffering from psychiatric or nervous system disorders can be treated, and further, social / emotional withdrawal or isolation that occurs in patients suffering from sleep disorders, such as insomnia, can be treated.

[0085] As detailed above, in patients suffering from social / emotional withdrawal or isolation in association with other conditions, treatment of the social / emotional withdrawal or isolation in accordance with the present invention leads to an improvement in the condition associated with the social / emotional withdrawal or isolation.

[0086] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0087] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, incomplete connections as networks reconnect. New, healthy functional connections are established, with lasting effects.

[0088] Thus, in accordance with the present invention, affecting these networks by the therapies described herein will result in an improvement in social / emotional withdrawal or estrangement, an improvement in a psychiatric or nervous system disorder if the treated patient suffers from that disorder, and an improvement in a sleep disorder, e.g., insomnia, if the treated patient suffers from that disorder.

[0089] To further support the clinical application of 5-MeO-DMT in patients suffering from social / emotional withdrawal or detachment, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric illness, noting specific improvements in social / emotional withdrawal or detachment that are also commonly observed in patients with other disorders.

[0090] 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. While TRD is a specific condition, as detailed below, the inventors have determined that certain clinical findings from the trial are relevant to the design of drugs for the treatment of other conditions associated with social / emotional withdrawal or isolation.

[0091] In clinical trials, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to various groups. Of interest in the context of the present invention are those receiving a single 12 mg dose and those receiving an intra-day individualized dosing regimen (IDR), which allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0092] Data collected included assessments of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was to demonstrate treatment efficacy through improvement in overall MADRS scores, the inventors focused on the items that comprise the various scales and noted that specific subscore items, such as those related to social / emotional withdrawal or detachment, are related to other conditions in which social / emotional withdrawal or detachment is based on similarly modulated functional connectivity within and / or between the default mode network, salience network, dorsal attention network, somatomotor network, and visual network.

[0093] Multiple patients within the pooled cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0094] More specifically, an aspect that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flattened affect. A further aspect that can be treated is reduced social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flattened affect. Furthermore, reduced social engagement is improved, i.e., reduced or eliminated.

[0095] The MADRS scale item "Inability to have emotions," which is particularly relevant to social / emotional withdrawal or detachment, describes the subjective experience of diminished interest in one's surroundings or in activities that usually provide pleasure. One has a reduced ability to respond emotionally appropriately to situations or people in one's surroundings.

[0096] A score of 0 indicates normal interest in surroundings and other people, while a score of 2 indicates a diminished ability to enjoy things that normally interest one. A score of 4 is assigned when 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.

[0097] Aggregate scores for the MADRS item "Inability to Have Emotions" across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 36. After two hours, the score decreased to 12, corresponding to a 24-point or 67% improvement. One day after treatment, the score decreased to 2, corresponding to a 34-point or 94% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 30-point or 83% improvement.

[0098] Scores for the MADRS item "Inability to Have Emotions" were compiled across all four patients in the 12 mg group, with a baseline of 16. After two hours, the score had decreased to 9, corresponding to a 7-point or 44% improvement. On day 1 after treatment, the score had decreased to 1, corresponding to a 15-point or 94% improvement. On day 7 after treatment, the score had decreased to 1, corresponding to a 15-point or 94% improvement.

[0099] BPRS scale items that are particularly relevant to social / emotional withdrawal or detachment are "inability to have emotions" and "flattened emotions."

[0100] The BPRS item "Emotional Withdrawal" 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 affective engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but the individual spontaneously engages with the interviewer most of the time. 3- Mild. Lack of emotional engagement is indicated by a noticeable inability to return feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4- Moderate. Emotional contact is absent for most of the interview because the subject does not respond in detail, is unable to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic tendencies. 5- Moderately severe. Similar to '4', but emotional contact is absent for the majority of the interview. 6- Severe. Actively avoids emotional involvement. Often does not respond or gives yes / no responses (not solely due to paranoia). 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 the interview or not respond at all.

[0101] Scores for the BPRS item "Emotional Withdrawal" were compiled with a baseline of 13. After 3 hours, the score decreased to 8, corresponding to a 5-point or 38% improvement. After 1 day of treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement. After 7 days of treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement.

[0102] The BPRS "emotional withdrawal" score for the 12 mg group was compiled from a baseline of 13. After 3 hours, the score had decreased to 11, corresponding to a 2-point or 15% improvement. After 1 day of treatment, the score had decreased to 8, corresponding to a 5-point or 38% improvement. After 7 days of treatment, the score had decreased to 6, corresponding to a 7-point or 54% improvement.

[0103] The BPRS item "Flat Affect" relates to a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- No emotional flattening. 2- Very mild. Emotional range is somewhat subdued or reserved, but facial expression and vocal tone are within the normal range and appropriate. 3- Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous and appropriate emotional responses are rare. Voice tone is somewhat monotonous. 4- Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressions of emotion or gestures usually return to a flat affect. 5- Moderately severe. The range of emotion is extremely reduced, the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expression rarely changes. The tone of voice is monotonous most of the time. 6- Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression is unchanging. Voice tone is monotonous most of the time. 7- Most severe. Virtually no emotional range or expression, stiff movements, monotonous tone of voice throughout the entire time.

[0104] Scores for the BPRS item "flat affect" were compiled, with a baseline of 15. After 3 hours, the score had decreased to 11, corresponding to a 4-point or 27% improvement. One day after treatment, the score had decreased to 8, corresponding to a 7-point or 47% improvement. Seven days after treatment, the score had decreased to 8, corresponding to a 7-point or 47% improvement.

[0105] The BPRS "flat affect" score for the 12 mg group was compiled from a baseline of 11. After 3 hours, the score had decreased to 8, corresponding to a 3-point or 27% improvement. After 1 day of treatment, the score had decreased to 6, corresponding to a 5-point or 45% improvement. After 7 days of treatment, the score had decreased to 5, corresponding to a 6-point or 55% improvement.

[0106] Thus, scores on scales particularly related to social / emotional withdrawal or detachment, i.e., "unable to have emotions" (MADRS), "emotional withdrawal" (BPRS), and "flattened affect" (BPRS), are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat social / emotional withdrawal or detachment in patients, particularly those suffering from psychiatric or nervous system disorders, or sleep disorders, such as insomnia.

[0107] Thus, in accordance with the present invention, treating a patient suffering from social / emotional withdrawal or isolation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or isolation.

[0108] Active Agent The above discussion indicates that social / emotional withdrawal or distancing itself presents a significant disease burden and merits appropriate treatment.

[0109] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of social / emotional withdrawal or isolation, improving the condition overall.

[0110] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families, 5-HT1 through 5-HT7, with several subtypes, have been described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelic drugs" and are primarily characterized by their 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), while other effects such as sedation, narcosis, or hyperstimulation are minimal.

[0111] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0112] 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 minor amine-associated receptors.

[0113] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0114] 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 experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three 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 (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0115] 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.

[0116] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0117] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from that of other hallucinogenic compounds.

[0118] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0119] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0120] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has enhanced affinity for the 5-HT1A receptor and acts as a potent agonist. Psilocin and DMT contribute more to 5-HT2A binding than 5-MeO-DMT, with the latter of the three compounds showing the greatest difference between their affinities for 5-HT2A and 5-HT1A. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than the other two compounds.

[0121] 5-HT1A receptor agonism has been reported to reduce impulsivity and aggression, while 5-HT2A receptor agonism may short-term increase these same traits. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0122] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depression, seasonal affective disorder, and bipolar disorder (BD), including bipolar I disorder and bipolar II disorder, psychotic disorders, including schizophrenia, or personality disorders, including schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0123] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate heavy use of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD).

[0124] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0125] 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.

[0126] 5-MeO-DMT can induce peak experiences, characterized by a shift in emotional perspective described as a "loss of self," which often leads to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after inhalation, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific modulation of resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0127] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. We have demonstrated that 5-MeO-DMT inhibits the 5-HT7 receptor by using recombinant human 5-HT7 receptors as a radioligand.3 Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM.

[0128] Thus, in addition to the 5-HT1A and 5-HT2A receptors described above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0129] 5-HT7 receptors have roles in neurogenesis, synaptogenesis and dendritic spine formation, and are involved in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0130] 5-HT7 receptors are particularly expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0131] The suprachiasmatic nucleus (SNU) 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, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders reveals modulation of functional connectivity between the SNU and regions within the default mode network.

[0132] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the function of this receptor in regulating the sleep / wake cycle, and the inventors believe this will allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0133] 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, including "resetting" the functional connectivity of networks and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0134] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, in addition to the binding to the 5-HT1A receptor, as two mediators of the effects of 5-MeO-DMT, including "resetting" functional network connectivity and neuroplasticity effects, may enable it to exert beneficial effects in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor retardation, negative thinking, or sleep disorders. This is supported by the clinical results demonstrated in the studies referred to herein.

[0135] Another characteristic of 5-MeO-DMT is its short half-life.

[0136] 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.

[0137] We investigated the pharmacokinetic properties of 5-MeO-DMT and found rapid absorption and distribution of inhaled 5-MeO-DMT, with peak concentrations and pharmacological effects observed during and immediately after administration.

[0138] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. Titrating doses as disclosed herein does not result in accumulation, and thus does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0139] The properties of 5-MeO-DMT make this compound particularly suitable for treating social / emotional withdrawal or isolation, especially in patients suffering from psychiatric or neurological disorders.

[0140] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0141] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0142] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0143] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

[0144] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0145] 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.

[0146] 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 on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0147] Methods for preparing these compounds are known in the art.

[0148] 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, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0149] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0150] Prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used in accordance with the present invention. 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 pharmaceutically acceptable salt thereof, the reference can be substituted for a 5-MeO-DMT prodrug or a salt thereof.

[0151] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0152] 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.

[0153] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 , and R 4 is defined as above.

[0154] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0155] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitriloacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitriloacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0156] Methods for preparing the prodrugs described herein are known in the art.

[0157] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0158] 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.

[0159] Mode of administration A 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 administration route is inhalation. Preferably, a therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0160] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0161] Buccal or sublingual administration can also be by a pharmaceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in formulations commonly known in the art (e.g., tablets, films, sprays, creams).

[0162] Administration is typically via inhalation of an aerosol. Such an aerosol contains (a) a pharmaceutically acceptable gas and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / L to about 18 mg / L (e.g., 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). The pharmaceutically acceptable gas is preferably air.

[0163] The aerosol particles preferably contain less than 1 wt. % impurities, particularly less than 0.5 wt. % impurities, and more preferably less than 0.5 wt. % 5-MeO-DMT decomposition products, particularly 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.

[0164] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0165] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0166] 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.

[0167] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically 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.

[0168] A thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via air passing over the layer, or alternatively, a thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via the solid support.

[0169] 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.

[0170] 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.

[0171] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. The 5-MeO-DMT and a pharmaceutically 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.

[0172] The aerosol useful in the present invention can be formed using thermal energy. When using thermal energy to form an 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 systemically deliver the compound to a patient 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 exposure duration); and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0173] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically 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 to a defined extent, preferably nearly completely or completely, that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharmaceutically 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 a single 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.

[0174] 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) briefly exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature, and c) providing a controlled amount of air so that an aerosol is formed.

[0175] 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 formed 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) can be delivered to a patient by a single inhalation.

[0176] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, which contain less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT degradation product drug by aerosol volume and can be delivered to a patient by a single inhalation, is achieved by specifying 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 the temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by the air flow rate and duration of the air flow).

[0177] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, whereby the air is heated. The temperature of the heated air passing over the thin layer can range from about 180°C to about 260°C. The temperature of the air passing over the thin layer can be, in particular, about 210°C.

[0178] Alternatively, the thin layer of 5-MeO-DMT can be 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.

[0179] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is highly pure, being at least 99%, preferably at least 99.5% pure.

[0180] 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, and more preferably about 4 mg to about 20 mg. Specific effective amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Specific preferred amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0181] The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, a cylinder less than 1.0 mm in diameter, a box 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 high surface area to volume ratio (e.g., greater than 100 per meter) and a high surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0182] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in 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 (approximately 400 per meter).

[0183] Several different materials are used to construct solid supports. 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.

[0184] 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), and PEG-1000 (Sigma, St. Louis, Mo.). 2 Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0185] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, particularly less than about 7.5 μm, and the thickness of the thin layer can range from about 0.1 μm to about 10 μm, particularly from 0.3 μm to 7.5 μm.

[0186] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of 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 airflow is selected so that the total aerosol volume does not exceed about 3 liters, which is preferably between about 1 liter and 3 liters (e.g., between 2 liters and 3 liters). For example, at an airflow rate of about 6 liters per minute, the duration of the airflow should be less than about 30 seconds. A specific effective airflow rate and duration is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective airflow rate and duration is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective airflow rate and duration 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.

[0187] The aerosol generation rate is greater than 0.1 mg / sec.

[0188] 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).

[0189] 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, and 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.

[0190] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT degradation products, preferably less than 0.2% wt of 5-MeO-DMT degradation products.

[0191] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include 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) containing aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) containing aerosol particles characterized by less than 1% impurities and less than 0.5% wt 5-MeO-DMT degradation products; and 3) capable of being delivered to a patient by a single inhalation.

[0192] Those skilled in the art, knowing the aerosol characteristics and aerosolization conditions defined in the present invention, can identify a suitable vaporization device or system that can achieve the required aerosol characteristics. Examples of such suitable vaporization devices or systems include the Volcano Medic Vaporization System (Storz & Bickel, Germany, for example, as disclosed in EP 0 933 093 B1 and EP 1 884 254 B1 and registered Community design 003387299-0001), which includes a dosage capsule with a related drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA, for example, as disclosed in 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.

[0193] Dosing regimen The present invention also provides dose ranges, specific doses, as well as dosing regimens (administration schemes).

[0194] The present invention is based in part on the inventors' conclusion that the occurrence of an acute hallucinogenic climax following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof causally facilitates, or at least serves as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from social / emotional withdrawal or detachment, particularly in patients suffering from one or more of the aspects defined above.

[0195] Thus, achieving a peak experience more rapidly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to hallucinogens and dosing regimens tested to date would result in a superior therapeutic profile.

[0196] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no attenuation or disappearance of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily) designed to increase the incidence of peak experiences and thereby enhance therapeutic efficacy. 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), induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no recollection 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 at higher doses, thereby positively influencing the experience at that higher dose. 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.

[0197] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate and modulate the reproducibility of peak experiences, and to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the slow 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), which may last for several days.

[0198] Patients suffering from social / emotional withdrawal or distancing, as defined herein, are treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0199] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (i.e., the patient is not receiving any other treatment for social / emotional withdrawal or isolation).

[0200] The dosage of 5-MeO-DMT administered to a patient suffering from social / emotional withdrawal or isolation, as defined herein, 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 effective amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Note that when a range, such as "about 1 mg to about 25 mg," is provided herein, the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned solely for the sake of brevity.

[0201] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from social / emotional withdrawal or isolation, using a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0202] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from social / emotional withdrawal or isolation with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, comprising a clinical response occurring by about 2 hours after administration of 5-MeO-DMT, for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0203] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from social / emotional withdrawal or isolation, using a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0204] 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 to 7 doses, the interval between each dose within each treatment block being at least about 1 hour and not more than about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0205] 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.

[0206] 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 to 3 doses, with the interval between each dose within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0207] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and 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 effective amounts include, 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.

[0208] 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.

[0209] 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 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, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0210] 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 increase 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.

[0211] 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 peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0212] 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 with 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 peak 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 experiences a hallucinogenic peak experience at a dose of 18 mg, and therefore the highest dosage in the first treatment block is 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 18 mg.

[0213] 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 a first treatment block, and 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 peak experience within that treatment block 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. Specific amounts that have been 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.

[0214] It will be understood that pharmaceutically 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.

[0215] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0216] The occurrence of a "psychedelic 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 Mystical Experience Questionnaire-Revised (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0217] The occurrence of a "psychedelic 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).

[0218] In accordance with the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also known as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, scored on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control did it make you feel? 3. How profound (i.e., meaningful) was the experience?

[0219] Treating social / emotional withdrawal or isolation and sleep disorders A sleep disorder refers to any condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder. Sleep disorders affect a person's ability to function adequately while awake and are associated with patterns of high negative affect and low positive affect.

[0220] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Normal human sleep involves four to five cycles each night, with non-REM and REM sleep alternating during each cycle. Early in the night, non-REM sleep is deeper and occupies a disproportionately long time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle allocated to REM sleep.

[0221] Normal, healthy sleep consists of different phases, as outlined above, that progress in a sequential, tightly regulated sequence throughout the night.

[0222] Disruption of this tight regulation leads to sleep disorders.

[0223] Common forms of sleep disorders include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders). In a broad sense, fatigue can also be considered a sleep disorder.

[0224] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep; frequently waking during the night and having difficulty falling asleep again; waking too early in the morning or having unrefreshing sleep; and / or have at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, concentration problems, or accidents at work or while driving.

[0225] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. Sleep drunkenness involves difficulty transitioning from sleep to wakefulness. Individuals experiencing sleep drunkenness report waking up feeling confused, disoriented, sluggish, and repeatedly returning to sleep.

[0226] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances resulting from a modulation of an individual's internal circadian rhythm or a mismatch between that circadian rhythm and desired or required work or social schedules. This dyssynchrony can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during desired wakefulness is impaired, and intermittent attempts to return to a normal sleep schedule are unsuccessful.

[0227] Parasomnias refer to various forms of sleep disorders characterized by abnormal behaviors or physiological activities (such as sleepwalking or nightmares) that a person experiences before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0228] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of respiratory muscles and the brain. These sleep disorders, which potentially have a significant impact on sleep and blood oxygen and carbon dioxide balance, manifest as chronic snoring, sleep apnea, sleep-related hypoventilation, and / or hypoxemia. In some cases, breathing is abnormal even during wakefulness. Reduced airflow causes intermittent hypoxia, resulting in microarousals or arousals, resulting in sleep fragmentation and excessive daytime sleepiness. Inflammation and endothelial dysfunction ensue, reducing vascular elasticity and promoting clotting, predisposing individuals to arteriosclerosis, which, along with reduced oxygenation, can lead to heart and brain damage.

[0229] In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements interfere with sleep or sleep onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0230] Fatigue describes a tired state that is not relieved by rest or sleep. Fatigue is a feeling of exhaustion, lethargy, or reduced energy, usually experienced as a weakness or depletion of physical or mental resources, and is characterized by a decreased ability to work and a decreased efficiency of response to stimuli. Fatigue is normal after periods of mental or physical exertion, but can also occur during periods of inactivity as a symptom of a health condition.

[0231] Not getting adequate amount or quality of sleep can lead to personality changes, exacerbate existing mental disorders, and even trigger the onset of new ones. Sleep disorders can also lead to social withdrawal, as sleep deprivation increases loneliness and reduces the desire for social interaction. Short sleep duration increases the likelihood of mood disorders by 55%. Anhedonia is a major symptom and mechanism by which sleep deprivation affects mood. Furthermore, insomnia can negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0232] Treatment for sleep disorders varies depending on their type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatment may also involve medication or psychological therapy.

[0233] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve relevant therapeutic benefits.

[0234] For patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not always improve the sleep disorder.

[0235] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of the associated sleep disorders. While most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while others may cause sleep disorders (Hutka et al. Association of Sleep Architecture and Physiology with Depressive Disorder and Antidepressants Treatment. Int J Mol Sci. 2021 Jan 29;22(3):1333., Abstract).

[0236] To assess sleep, parameters such as sleep time, sleep architecture, sleep latency, and wake frequency and duration can be measured throughout the night. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency measurements, or using self-reported metrics (questionnaires).

[0237] Polysomnography is a procedure that requires patients to be monitored overnight in a specialized clinic, during which a variety of functions are measured, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0238] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective metric to determine how long it takes a person to fall asleep during multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal; a mean sleep latency of less than 8 minutes indicates a sleep disorder. Concomitant analysis of brain activity can aid in further diagnosis of sleep disorders.

[0239] The sleep assessment questionnaire collects assessments of components of sleep quality, such as perceived depth of sleep, difficulty waking, and restfulness after sleep, as well as assessments of other factors that may affect sleep quality, such as comorbid conditions and medication use.

[0240] Assessment of qualitative aspects of the sleep experience is important because sleep complaints often persist despite normal quantitative measures of sleep.

[0241] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful for tracking patient progress. Therefore, patient-completed self-reported sleep questionnaires are an important pillar of the assessment of sleep disorders in clinical practice.

[0242] Various indices of sleep quality are known. The following indices include examples of questionnaires that assess overall sleep, as well as questionnaires that assess insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0243] Overall sleep quality can be assessed using, for example, the Sleep Quality Scale (SQS) and the Sleep-50 questionnaire.

[0244] The Sleep Quality Scale (SQS) is a comprehensive assessment tool that provides a general and efficient metric suitable for assessing sleep quality in various patient and research populations. Specific questions about daytime symptoms, such as difficulty with attention, concentration, or memory problems (item 15, "Because I don't get enough sleep, I have trouble thinking," item 19, "Because I don't get enough sleep, I make mistakes at work," item 21, "Because I don't get enough sleep, I forget things," and item 22, "Because I don't get enough sleep, I have trouble concentrating at work"), recovery after sleep, problems initiating and maintaining sleep, difficulty waking up, and sleep satisfaction, can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more severe sleep problems.

[0245] The SLEEP-50 questionnaire consists of 50 items designed to screen the general population for various types of sleep disorders. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and complaints and factors necessary for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a rating scale from 1 ("not at all true") to 4 ("very true") and asked to indicate how well the statement matches their experiences over the past month or another appropriate recall period.

[0246] The questionnaire requires that a specific subscale (e.g., insomnia) not only exceed a certain cutoff point, but also exceed the impact subscale to diagnose a sleep disorder (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46., table 4 for optimal cutoff values ​​and scoring procedures).

[0247] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0248] A common questionnaire for assessing sleep disturbances is the Pittsburgh Sleep Quality Index. Other instruments include the insomnia severity index and the Espie sleep disturbance questionnaire.

[0249] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced certain sleep difficulties over the past month or another suitable recall period.

[0250] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0251] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Details of the Pittsburgh Sleep Quality Index scoring methodology 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.

[0252] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A cutoff score of 5 for the overall score distinguishes between those with and without sleep problems. A overall score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0253] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0254] The Insomnia Severity Inventory (ISI) is a five-item questionnaire that addresses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning (item 3: "To what extent do you think your sleep problems interfere with daily functioning (e.g., daytime fatigue, ability to do work / daily chores, concentration, memory, mood, etc.)?"), how noticeable the respondent perceives their insomnia compared to others, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (= none) to 4 (= very). A higher total score corresponds to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 indicates "subthreshold insomnia," 15–21 indicates "clinical insomnia (moderate severity)," and 22–28 indicates "clinical insomnia (severe)" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012; Bastien et al. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001 Jul;2(4):297–307).

[0255] The typical recall period for an ISI is two weeks, although other suitable recall periods may be used herein.

[0256] Successful treatment is indicated by (i) a decrease in score, for example by a decrease of >7 points, especially >8 points; and preferably (ii) a decrease below the cut-off for clinically significant insomnia.

[0257] The Sleep Preoccupation Scale (SPS) is a 22-item self-report scale designed to assess daytime cognition in patients with insomnia. While researchers have frequently focused on nighttime thoughts and preoccupations when attempting to treat sleep disorders, a growing body of research suggests that daytime beliefs about sleep may be equally important to the insomnia experience. The SPS items assess two distinct domains: cognitive and behavioral consequences of sleep deprivation (e.g., negative thoughts and cognitions), and emotional consequences (e.g., worry and distress). This tool may be particularly useful for clinicians attempting to identify and treat the causes of their patients' sleep problems.

[0258] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ assesses restlessness / agitation, mental hyperactivity, impact of insomnia, and lack of sleep preparation, and specifically relates to beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate the extent to which a particular statement about insomnia applies to their experience. 1 means "not at all true," while 5 means "very true." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc. cit.; Espie et al. Insomniacs' attributions. Psychometric properties of the Dysfunctional Beliefs and Attitudes about Sleep Scale and the Sleep Disturbance Questionnaire. J Psychosom Res. 2000 Feb;48(2):141-8).

[0259] Successful treatment is indicated by a decrease in score.

[0260] Hypersomnia or excessive sleepiness can be assessed by the Epworth sleepiness scale, the Stanford sleepiness scale, or the Idiopathic Hypersomnia Severity Scale.

[0261] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. This questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stuck in traffic. Using a scale of 0 to 3 (0 meaning "never doze off" and 3 meaning "likely doze off"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies a level of daytime sleepiness that may become clinically problematic (A. Shahid et al., loc. cit. Johns et al., "A new method for measuring daytime sleepiness: the Epworth sleepiness scale." Sleep, 1991 Dec;14(6):540-5).

[0262] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 0 or below.

[0263] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment. The scale consists of only one item, requiring respondents to select one of seven statements that best describes their current perceived level of sleepiness. To assess sleepiness, a scale ranging from 1 (= motivated and active; alert; not sleepy) to 7 (= drowsy; likely to fall asleep easily; unable to stay awake) is used (A. Shahid et al., loc. cit.; Hoddes et al., The development and use of the Stanford sleepiness scale (SSS). Psychophysiology, 1972, 9, 150).

[0264] Successful treatment is indicated by a decrease in score.

[0265] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0266] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists and rates the frequency of parasomnias and includes outcome measures (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0267] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0268] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc. cit.; Netzer et al., Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999 Oct 5;131(7):485-91). An appropriate recall period can also be selected.

[0269] Successful treatment is indicated by a decrease in score.

[0270] A common questionnaire used to assess sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale (A. Shahid et al., loc. cit.; Walters et al.; International Restless Legs Syndrome Study Group 2003. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Medicine 4(2), pp. 121-132).

[0271] Treatment response can be assessed by a reduction in score.

[0272] Fatigue is commonly assessed, for example, by the FACES (Fatigue, Lethargy, Awareness, Energy, Sleepiness) scale.

[0273] The FACES (Fatigue, Lethargy, Alertness, Energy, Sleepiness) scale is a 50-item checklist for distinguishing between tiredness, sleepiness, and fatigue. Respondents indicate the extent to which they experienced each emotion or energy state over the past week or another appropriate recall period using a scale ranging from 0 ("not at all true") to 3 ("very true"). With the exception of the energy subscale, higher scores indicate more severe fatigue or tiredness (A. Shahid et al., loc. cit.; Shapiro et al., Development of an adjective checklist to measure five FACES of fatigue and sleepiness. Data from a national survey of insomniacs. J Psychopomp Res. 2002 Jun;52(6):467-73).

[0274] Effective treatment reduces tiredness and / or fatigue scores and increases energy subscale scores.

[0275] Treatment response can be assessed by the use of quantitative measures such as polysomnography or actigraphy, as described above, and / or questionnaires as described above. Depending on the respective sleep scale, a significant decrease or increase in the total score, or a significant decrease in prevalence, frequency, and impact on daily function, respectively, indicates that the sleep disorder has improved with treatment.

[0276] Common tests that assess social / emotional withdrawal or detachment, or aspects thereof, that can be used are, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), and the Personality Inventory for DSM-5 (PID-5) - Adult.

[0277] Resting-state fMRI has been widely applied to patients with sleep disorders to better understand the pathophysiology and potential compensatory mechanisms.

[0278] Modulation of the resting network can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0279] In patients with insomnia, dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain important regions that integrate emotional and physical states, and that dysfunctional connectivity with other brain regions may underlie patients' reduced vigilance, subjective distress, and sleep continuity.

[0280] For example, sleep deprivation in healthy subjects causes modulation of functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these modulations of brain functional connectivity somewhat resemble vulnerability patterns in patients with Alzheimer's disease.

[0281] The default mode network is affected in patients with hypersomnia: for example, idiopathic hypersomnia shows significant alterations in different DMN hubs—the precuneus and medial prefrontal cortex—and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0282] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disorders altered resting-state function in the cerebellum, which is involved in sleep regulation, and affected cognitive functions such as responsiveness and alertness. Furthermore, functional connectivity of the DMN was fundamentally different between morning- and evening-type circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may lead to alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases associated with circadian rhythm disorders.

[0283] Although functional brain imaging during a parasomnia event is technically challenging, precuneus differences have been observed in arousal disorders presenting with non-REM parasomnia.

[0284] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information, as well as monitoring movement. The precuneus is a subregion of the DMN. Therefore, the default mode network is affected in patients with parasomnia.

[0285] Resting-state fMRI studies in patients suffering from sleep-related breathing disorders such as obstructive sleep apnea (OSA) have demonstrated that prolonged exposure to oxidative stress, intermittent hypoxia, hypocapnia and hypercapnia, and sleep fragmentation, which are some of the main causes of OSA brain damage, can lead to significant deficits in global and regional connectivity, particularly in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0286] For example, sleep-related movement disorders such as periodic limb movements during sleep are reflected by modulation of the prefrontal motor control pathway, a subregion of the default mode network, and activity in the cerebellum and thalamus, accompanied by increased activation of the red nucleus and brainstem.

[0287] In many cases, the resting state networks involved in sleep regulation are also involved in social / emotional withdrawal or isolation. Thus, in accordance with the present invention, affecting these networks with a therapy according to the present invention will improve sleep disorders and, if the treated patient suffers from social / emotional withdrawal or isolation, will also improve social / emotional withdrawal or isolation.

[0288] Clinical data from studies of patients suffering from TRD or postpartum depression (PPD) support that sleep disorders can be successfully treated.

[0289] Studies involving administration of 5-MeO-DMT assessed the MADRS item "decreased sleep," which specifically reflects insomnia.

[0290] The MADRS item "Decreased Sleep" describes the experience of a decrease in the duration or depth of sleep compared to the subject's normal pattern when healthy. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, shallow, or disrupted sleep. A score of 4 means at least 2 hours of reduced or disrupted sleep. A score of 6 means less than 2-3 hours of sleep.

[0291] Aggregate scores for the MADRS item "Decreased Sleep" across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 25. On day 1 of treatment, the earliest time point at which treatment's impact on sleep could be assessed, the score decreased to 12, representing a 13-point or 52% improvement. On day 7 of treatment, the score decreased to 9, representing a 16-point or 64% improvement.

[0292] The combined MADRS "Decreased Sleep" score across all four patients in the 12 mg group had a baseline of 12. On post-treatment day 1, the score decreased to 10, corresponding to a 2-point or 17% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0293] Thus, scores on the scale item "decreased sleep," which is particularly relevant to sleep disorders, are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat patients suffering from sleep disorders, particularly psychiatric or nervous system disorders.

[0294] Treatment of patients suffering from sleep disorders, particularly insomnia, and associated social / emotional withdrawal or isolation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or isolation, leading to improvement of the sleep disorder, particularly insomnia.

[0295] In patients suffering from a sleep disorder, particularly insomnia, the reduction or elimination of social / emotional withdrawal or isolation is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0296] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from a sleep disorder, particularly insomnia, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, 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 pharmaceutically acceptable salt thereof.

[0297] In a patient suffering from a sleep disorder, particularly insomnia, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0298] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the SHAPS 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 pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0299] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0300] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the DARS 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 pharmaceutically acceptable salt thereof.

[0301] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0302] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with a sleep disorder, particularly insomnia, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period starting after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0303] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from a sleep disorder, particularly insomnia, is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0304] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with a sleep disorder, particularly insomnia, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0305] As mentioned above, social / emotional withdrawal or isolation is an important aspect for patients suffering from sleep disorder, especially insomnia.Therefore, improving social / emotional withdrawal or isolation also leads to improving sleep disorder, especially insomnia.Because social / emotional withdrawal or isolation also affects other aspects of sleep disorder, the inventors conclude that improving social / emotional withdrawal or isolation will further contribute to the overall improvement of sleep disorder, especially insomnia.

[0306] In the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation, clinical response may 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 by at least one level. Preferably, a decrease in the CGI-S by at least two levels and / or a score of 0. Particularly preferred is a decrease in the CGI-S by at least three levels and / or a score of 0.

[0307] Improvement in idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0308] Improvement in the idiopathic sleep disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in the CGI-S score of the patient who also suffers from associated social / emotional withdrawal or detachment, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the idiopathic sleep disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in the CGI-S 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 pharmaceutically acceptable salt thereof.

[0309] In one embodiment, improvement in idiopathic sleep disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0310] In the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0311] In the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation, improvement in the sleep disorder, as reflected 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 pharmaceutically acceptable salt thereof.

[0312] Improvement in the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation can also be assessed by any other measure that reflects changes in sleep quality or quantity, such as the Pittsburgh Sleep Quality Index (PSQI), as described above.

[0313] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0314] Improvement in the idiopathic sleep disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in PSQI total score, particularly a decrease to 5 or less, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period extends from the time the acute hallucinatory climax experience abates after the last administration to the time of assessment. Such improvement in the idiopathic sleep disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in PSQI total score, preferably persists until at least 6 days; particularly until at least 14 days; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period extends from the time the acute hallucinatory climax experience abates after the last administration to the time of assessment.

[0315] Improvement in idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in PSQI total score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period spans from the time the acute hallucinogenic high experience abated after the last administration to the time of assessment.

[0316] Social / emotional withdrawal or isolation and sleep disorders, especially insomnia, are closely related to mental and nervous system disorders. Both social / emotional withdrawal or isolation and sleep disorders, especially insomnia, are closely related to mental or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depression, anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); It occurs in pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0317] Social / emotional withdrawal or isolation and sleep disorders, particularly insomnia, also occur in medical health conditions that are linked to related mental or neurological conditions, such as traumatic brain injury (TBI).

[0318] Treatment according to the invention leads to an improvement in both social / emotional withdrawal or isolation and sleep disorders, particularly insomnia, as well as in associated psychiatric or neurological disorders such as those listed above.

[0319] Treatment of social / emotional withdrawal or isolation and mental and nervous system disorders In the case of patients suffering from social / emotional withdrawal or isolation associated with a psychiatric or neurological disorder, treatment of the social / emotional withdrawal or isolation according to the present invention leads to an improvement in the condition associated with the social / emotional withdrawal or isolation.

[0320] Although social / emotional withdrawal or detachment can be considered a condition worthy of treatment independent of other conditions, disorders, or symptoms that an individual may suffer from, several psychiatric and neurological disorders are associated with social / emotional withdrawal or detachment. Notably, the relationship between social / emotional withdrawal or detachment and psychiatric disorders is bidirectional. Not only can psychiatric disorders contribute to a patient's emotional state of social / emotional withdrawal or detachment, but social / emotional withdrawal or detachment can also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0321] The resting-state networks often involved in social / emotional withdrawal or detachment are also involved in the conditions listed above.

[0322] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption resets pathological, incomplete brain connections as the network reconnects. New, healthy functional connections are established, with lasting effects.

[0323] Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0324] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0325] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present for the same two-week period and representing a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

[0326] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0327] Patients suffering from disorders characterized by depressive episodes often also suffer from social / emotional withdrawal or detachment.

[0328] Social / emotional withdrawal or detachment is included in the diagnostic criteria for disorders characterized by major depressive episodes and may be assessed as part of the MADRS or BPRS assessment.

[0329] 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. Higher MADRS scores indicate more severe depression.

[0330] The items considered are outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, inability to feel emotions, pessimistic thoughts, and suicidal thoughts, each of which is given a score of 0 to 6. The total score ranges from 0 to 60.

[0331] The MADRS item "Inability to have emotions" describes the subjective experience of diminished interest in one's surroundings or in activities that normally give pleasure. The ability to respond with appropriate emotions to surrounding situations or people is diminished. It is rated 0 if interest in one's surroundings and others is normal; it is rated 1, 2, or 3 if there is a diminished ability to enjoy normal interests; it is rated 3, 4, or 5 if there is a loss of interest in one's surroundings, emotions, or friends and acquaintances; and it is rated 6 if one experiences emotional numbness, is unable to feel anger, deep sadness, or joy, and is completely or painfully unable to care for close relatives and friends.

[0332] The "emotional withdrawal" item on the Brief Psychiatric Rating Scale (BPRS) reflects a deficit in the patient's relationship with the interviewer and the interview situation. The interviewer assesses only the extent to which the patient gives the impression of not being able to emotionally connect with others in the interview situation.

[0333] The BPRS item "flat affect" describes a decreased emotional tone and a clear lack of usual affect or engagement.

[0334] Social / emotional withdrawal or detachment, or aspects thereof, such as anhedonia, in patients suffering from disorders characterized by depressive episodes can be assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0335] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity are observed within and / or between multiple brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal.

[0336] Treatment of patients suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, and associated social / emotional withdrawal or detachment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the disorder characterized by depressive episodes.

[0337] In patients suffering from a disorder characterized by a depressive episode, the reduction or elimination of social / emotional withdrawal or detachment is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0338] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from a disorder characterized by a depressive episode occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from a disorder characterized by a depressive episode 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 pharmaceutically acceptable salt thereof.

[0339] In patients suffering from a disorder characterized by depressive episodes, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS item "inability to have emotions" about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0340] The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the MADRS item "Inability to Have Emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the MADRS item "Inability to Have Emotions," 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 pharmaceutically acceptable salt thereof.

[0341] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the score on the BPRS item "Emotional Withdrawal" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0343] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the score on the BPRS item "Flat Affect" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] The reduction or elimination of social / emotional withdrawal or detachment, particularly flat affect, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the BPRS item "flat affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the score on the BPRS item "flat affect," in patients suffering from a disorder characterized by depressive episodes, 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 pharmaceutically acceptable salt thereof.

[0345] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by depressive episodes is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0346] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in patients suffering from a disorder characterized by depressive episodes, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0347] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0349] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0350] In patients with a disorder characterized by depressive episodes, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0351] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0352] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0353] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0354] A reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0355] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from a disorder characterized by a depressive episode is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0356] In patients with a disorder characterized by depressive episodes, reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Domain Detachedness Trait, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Domain Detachment, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0357] As mentioned above, social / emotional withdrawal or isolation is closely related to the disorder characterized by depressive episodes.Therefore, the improvement of social / emotional withdrawal or isolation also leads to the improvement of the disorder characterized by depressive episodes.Because social / emotional withdrawal or isolation also affects other aspects of the disorder characterized by depressive episodes, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of the disorder characterized by depressive episodes.

[0358] Improvement in a disorder characterized by depressive episodes in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] Improvement in the disorder characterized by depressive episodes in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the disorder characterized by depressive episodes in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S 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 pharmaceutically acceptable salt thereof.

[0360] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest, which affect the way a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0361] Patients with MMD may have a treatment-resistant form of the disorder.

[0362] Patient may suffer from treatment-resistant disease.Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy; for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses.At least two previous treatment courses are particularly administered during depressive episodes.

[0363] Anhedonia is a core symptom and key feature of MDD as outlined in the DSM-5.

[0364] Depressive symptoms are also associated with decreased time spent in social interactions. Social withdrawal is common in patients with MDD and is associated with suicidal ideation.

[0365] Social / emotional withdrawal or detachment in patients with MDD may be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects of it, can be further assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0366] In patients with MDD, dysfunctional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network, is observed, and functional connectivity differs significantly from that observed in healthy controls.

[0367] Treating patients suffering from MDD, including treatment-resistant forms of the disorder, and the associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the MDD.

[0368] The patient may have moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. It is further contemplated that the patient may have severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or greater.

[0369] In a patient with MDD, reduction or elimination of social / emotional withdrawal or estrangement is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0370] The reduction or elimination of social / emotional withdrawal or isolation in a patient with MDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation 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 pharmaceutically acceptable salt thereof.

[0371] In patients with MDD, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS item "inability to have emotions" about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients with MDD, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients with MDD, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," 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 pharmaceutically acceptable salt thereof.

[0373] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with MDD is reflected by at least an improvement in the score on the BPRS item "Emotional Withdrawal" about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with MDD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with MDD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0375] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in a patient with MDD is reflected by at least an improvement in the score on the BPRS item "Flat Affect" about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0376] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with MDD, as reflected by an improvement in the score on the BPRS item "Flat Affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with MDD, as reflected by an improvement in the score on the BPRS item "Flat Affect," 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 pharmaceutically acceptable salt thereof.

[0377] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with MDD is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0378] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with MDD, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in patients with MDD, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment.

[0379] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with MDD is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0380] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with MDD, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients with MDD, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0381] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with MDD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0382] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0383] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with MDD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0384] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0385] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with MDD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0386] A reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0387] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with MDD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0388] The reduction or elimination of social / emotional withdrawal or detachment in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with MDD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, 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 pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment.

[0389] As mentioned above, social / emotional withdrawal or isolation is closely related to MDD.Therefore, the improvement of social / emotional withdrawal or isolation will also lead to the improvement of MDD.Because social / emotional withdrawal or isolation also affects other aspects of MDD, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation will also contribute to the overall improvement of MDD.

[0390] Improvement in MDD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0391] Improvement in MDD in patients who also suffer from social / emotional withdrawal or isolation, as reflected by a decrease in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in MDD in patients who also suffer from associated social / emotional withdrawal or isolation, as reflected by a decrease in CGI-S 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 pharmaceutically acceptable salt thereof.

[0392] A further aspect of MDD in patients who also suffer from associated social / emotional withdrawal or isolation that can be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to MDD patients who also suffer from associated social / emotional withdrawal or isolation to reduce or eliminate suicidal ideation in said patients.

[0393] In the above-mentioned clinical study of patients suffering from TRD with administration of 5-MeO-DMT, the MADRS item "suicidal ideation" was assessed, among other things.

[0394] "Suicidal ideation" refers to feelings that life is not worth living, that a natural death is desirable, that one has suicidal thoughts, and / or is preparing to commit suicide. A suicide attempt, in itself, should not affect the rating of this MADRS item.

[0395] A score of 0 means the patient is enjoying life. A score of 2 is assigned if the PPD patient is tired of life and has fleeting suicidal thoughts. A score of 4 means the patient feels they would be better off dead, suicidal thoughts are common, and suicide is considered 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.

[0396] This MADRS scale item is particularly relevant to suicidal ideation.

[0397] In the study group receiving the individualized dosing regimen, the aggregated MADRS item "suicidal ideation" score across all eight patients had a baseline of 11. After two hours, the score decreased to 3, corresponding to an 8-point or 73% improvement. One day after treatment, the score decreased to 1, corresponding to a 10-point or 91% improvement. Seven days after treatment, the score decreased to 3, corresponding to an 8-point or 73% improvement.

[0398] Aggregating scores for the MADRS item "Suicidal Ideation" across all four patients in the 12 mg group, the baseline was 8. After 2 hours, the score had decreased to 3, corresponding to a 5-point or 63% improvement. On the first post-treatment day, the score had decreased to 5, corresponding to a 3-point or 38% improvement. On the seventh post-treatment day, the score had decreased to 7, corresponding to a 1-point or 13% improvement.

[0399] Thus, scores on the "suicidal ideation" scale, a measure specifically related to suicidal ideation, significantly improved in patients on at least the individualized dosing regimen. We conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with MDD.

[0400] Thus, in accordance with the present invention, treating a patient suffering from MDD associated with social / emotional withdrawal or isolation reduces or eliminates suicidal ideation.

[0401] Reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or detachment is reflected by at least an improvement in the score for suicidal ideation on the MADRS item at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0402] The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or isolation, as reflected by at least an improvement in the MADRS item score for suicidal ideation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or isolation, as reflected by at least an improvement in the MADRS item score for suicidal ideation, 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 pharmaceutically acceptable salt thereof.

[0403] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT or a pharmaceutically acceptable salt thereof can be administered to patients suffering from MDD, which is associated with social / emotional withdrawal or detachment, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0404] Preferably, patients suffering from MDD associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0405] Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). BD is a relapsing, chronic illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0406] 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-blown 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.

[0407] Patients suffering from BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0408] Patient may suffer from treatment-resistant disease.Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy; for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses.At least two previous treatment courses are particularly administered during depressive episodes.

[0409] Different brain regions are involved in flat affect and emotional withdrawal in patients with bipolar I and bipolar II disorder.

[0410] In a study of 197 adolescents with bipolar disorder, anhedonia was present in 90.9% of patients during severe depressive episodes, and symptom severity was significantly associated with the severity of the disorder.

[0411] In patients with treatment-resistant bipolar depression, a single dose of 0.5 mg kg -1 Ketamine infusions rapidly reduced levels of anhedonia; a single infusion had an effect within 40 minutes and lasted for up to 14 days. Positron emission tomography (PET) scans of a subgroup of these individuals found that the anti-anhedonia effect was partially driven by glucose metabolism in the dorsal anterior cingulate cortex (an element of the DAN) and putamen (part of the basal ganglia RSN) of the brain.

[0412] Social / emotional withdrawal or detachment in patients with BD may be assessed as part of the MADRS, BPRS, or BDRS assessment. Social / emotional withdrawal or detachment, or at least aspects of it, can be further assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0413] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated for clinical use by trained raters. BDRS items are based on a clinical interview and assess the severity of depressive and / or mixed symptoms exhibited by the patient in the current and past few days. If there is a discrepancy between the current and past few days' symptoms, the current symptoms must be reflected in the assessment. The scale contains 20 questions, with a maximum score of 60. Higher scores indicate greater severity.

[0414] Questions address depressed mood, sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; flat affect; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor impulsivity; increased speech; and agitation.

[0415] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3.

[0416] The BDRS item "Decreased Social Engagement" reports decreased social and interpersonal engagement or interaction. Decreased social engagement is scored as 0 if normal; 1 (mild) if social engagement is slightly reduced and social and interpersonal functioning is unimpaired; 2 (moderate) if social engagement is clearly reduced with some functional sequelae, e.g., avoidance of some social engagement or conversation; and 3 (severe) if social interaction is significantly reduced or almost all forms of social contact are avoided, e.g., refusing to answer the phone or meet with friends or family.

[0417] The BDRS item "anhedonia" concerns a subjective reduction in the ability to experience pleasure in usual activities. Anhedonia is scored as 0 if there is no subjective reduction in the ability to experience pleasure in everyday activities; 1 (mild) if pleasure from usual pleasurable activities is slightly reduced; 2 (moderate) if pleasure from usual pleasurable activities is significantly reduced, with some maintained pleasure from isolated activities; and 3 (severe) if there is a complete inability to experience pleasure.

[0418] Flat affect is the subjective feeling of a decrease in the intensity or range of emotions or feelings. Flat affect is scored as 0 if there is no subjective sense of a decrease in the intensity or range of emotions or feelings, 1 (mild) if there is a slight contraction in the range of emotions or a transient decrease in the range or intensity of emotions, 2 (moderate) if there is a significant contraction 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 contraction in the range of emotions or an inability to experience normal emotions.

[0419] Patients with bipolar disorder exhibit abnormal intrinsic organization and interconnectivity of resting-state networks. Compared with healthy controls, resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network. In particular, altered functional connectivity within the default mode network has also been observed in patients with sleep disorders.

[0420] Treatment of patients suffering from BD, including treatment-resistant forms of the disorder, and associated social / emotional withdrawal or isolation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or isolation, leading to improvement of BD.

[0421] Typically, patients with BD, whether diagnosed with bipolar II disorder or bipolar I disorder, are suffering from a current major depressive episode.

[0422] The severity of the current major depressive episode may be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient's total score may be 19 or greater, such as 24 or greater, especially 37 or greater.

[0423] 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.

[0424] In a patient suffering from bipolar disorder, reduction or elimination of social / emotional withdrawal or detachment is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0425] The reduction or elimination of social / emotional withdrawal or isolation in a patient with BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient with BD 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 pharmaceutically acceptable salt thereof.

[0426] In patients with BD, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS inability to have emotions item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0427] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in patients with BD, as reflected by an improvement in the score on the MADRS item "inability to have emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in patients with BD, as reflected by an improvement in the score on the MADRS item "inability to have emotions," 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 pharmaceutically acceptable salt thereof.

[0428] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient suffering from BD is reflected by at least an improvement in the score on the BPRS item "Emotional Withdrawal" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0429] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with BD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with BD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0430] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly flat affect, in patients with BD is reflected by at least an improvement in the score on the BPRS item "Flat Affect" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0431] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with BD, as reflected by an improvement in the score on the BPRS item "flat affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with BD, as reflected by an improvement in the score on the BPRS item "flat affect," 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 pharmaceutically acceptable salt thereof.

[0432] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly decreased social engagement, in a patient suffering from BD is reflected by at least an improvement in the score on the BDRS item "Decreased Social Engagement" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0433] The reduction or elimination of social / emotional withdrawal or isolation, particularly reduced social engagement, in patients with BD, as reflected by an improvement in the score on the BDRS item "reduced social engagement," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation, particularly reduced social engagement, in patients with BD, as reflected by an improvement in the score on the BDRS item "reduced social engagement," 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 pharmaceutically acceptable salt thereof.

[0434] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD is reflected by at least an improvement in the score on the BDRS item "Anhedonia" about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0435] The reduction or elimination of social / emotional withdrawal or detachment, particularly reduced anhedonia, in patients with BD, as reflected by an improvement in the score on the BDRS item "Anhedonia," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly reduced anhedonia, in patients with BD, as reflected by an improvement in the score on the BDRS item "Anhedonia," 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 pharmaceutically acceptable salt thereof.

[0436] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly flat affect, in a patient suffering from BD is reflected by at least an improvement in the score on the BDRS item "Flat Affect" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours, at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0437] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with BD, as reflected by an improvement in the score on the BDRS item "Flat Affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with BD, as reflected by an improvement in the score on the BDRS item "Flat Affect," 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 pharmaceutically acceptable salt thereof.

[0438] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0439] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in patients with BD, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment.

[0440] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0441] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients with BD, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0442] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from BD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0443] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0444] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with BD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0445] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0446] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient suffering from BD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0447] A reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0448] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with BD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0449] The reduction or elimination of social / emotional withdrawal or detachment in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with BD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, 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 pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment.

[0450] As mentioned above, social / emotional withdrawal or isolation is closely related to BD.Therefore, the improvement of social / emotional withdrawal or isolation will also lead to the improvement of BD.Because social / emotional withdrawal or isolation also affects other aspects of BD, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation will further contribute to the overall improvement of BD.

[0451] Improvement in BD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0452] Improvement in BD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in bipolar disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S 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 pharmaceutically acceptable salt thereof.

[0453] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, can be administered to patients suffering from bipolar disorders, including bipolar I disorder and bipolar II disorder, which are associated with social / emotional withdrawal or detachment, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0454] Preferably, patients suffering from bipolar disorders, including bipolar I disorder and bipolar II disorder, which are associated with social / emotional withdrawal or detachment, do not experience treatment-emergent mania or hypomania.

[0455] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks after delivery. Over 50% of women experience a brief period of low mood or tearfulness after giving birth, but a subset of women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0456] Patients with PPD may suffer from a treatment-resistant form of the disorder.

[0457] An analysis of data from 663 women with perinatal depression found that anhedonia and anxiety were prominent symptoms eight weeks after giving birth.

[0458] Social isolation is one of five identified aspects that correlate with and predict maternal depressive symptoms.

[0459] PPD is also known as perinatal-onset major depressive disorder.According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when the symptoms of major depressive disorder (MDD) begin during pregnancy or within 4 weeks of delivery.Therefore, PPD patients also suffer from social / emotional withdrawal or detachment, especially anhedonia.

[0460] Social / emotional withdrawal or detachment in patients with PPD may be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects of it, can be assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0461] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with dysfunction in resting-state network connectivity within and / or between, for example, the default mode network and the frontoparietal network.

[0462] Treating patients suffering from PPD and associated social / emotional withdrawal or detachment, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the PPD.

[0463] The patient may have moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. It is further contemplated that the patient may have severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0464] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0465] Additionally, patients treated according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0466] Additionally, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0467] In patients with PPD, reduction or elimination of social / emotional withdrawal or estrangement is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0468] The reduction or elimination of social / emotional withdrawal or isolation in a patient with PPD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient with PPD 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 pharmaceutically acceptable salt thereof.

[0469] In patients with PPD, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS inability to have emotions item at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0470] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in patients with PPD, as reflected by an improvement in the score on the MADRS item "Inability to Have Emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in patients with PPD, as reflected by an improvement in the score on the MADRS item "Inability to Have Emotions," 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 pharmaceutically acceptable salt thereof.

[0471] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient with PPD is reflected by an improvement in the score on the BPRS item "Emotional Withdrawal" at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with PPD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with PPD, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0473] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly flat affect, in a patient with PPD is reflected by an improvement in the score on the BPRS item "Flat Affect" at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with PPD, as reflected by an improvement in the score on the BPRS item "flat affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with PPD, as reflected by an improvement in the score on the BPRS item "flat affect," 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 pharmaceutically acceptable salt thereof.

[0475] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from PPD is reflected by an improvement in the Snaith-Hamilton Psychological Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0476] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from PPD, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in a patient suffering from PPD, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment.

[0477] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with PPD is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0478] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with PPD, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in a patient with PPD, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0479] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from PPD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0480] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0481] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with PPD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0482] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0483] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient suffering from PPD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0484] A reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0485] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with PPD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0486] The reduction or elimination of social / emotional withdrawal or detachment in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with PPD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, 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 pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment.

[0487] As mentioned above, social / emotional withdrawal or isolation is closely related to PPD.Therefore, the improvement of social / emotional withdrawal or isolation is also connected to the improvement of PPD.Because social / emotional withdrawal or isolation also affects other aspects of PPD, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of PPD.

[0488] Improvement in PPD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] Improvement in PPD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PPD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S 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 pharmaceutically acceptable salt thereof.

[0490] Furthermore, social / emotional withdrawal or estrangement impairs maternal functioning.

[0491] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index was designed to measure functioning in the year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score of 0 to 6, with a maximum total score of 120. Higher scores indicate better maternal functioning.

[0492] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-infant communication, maternal emotional well-being, social support, control, and adjustment.

[0493] A BIMF score of 95 or less is considered herein to represent mild maternal dysfunction, a score of 80 or less is considered herein to represent maternal dysfunction, and a score of 65 or less is considered herein to represent severe maternal dysfunction.

[0494] The inventors determined that elevated scores on the MADRS item "inability to have emotions" and / or the BPRS items "emotional withdrawal" and "flat affect" negatively impact maternal functioning (maternal competence related to communicating with infant(s) and maternal self-care).

[0495] Increased scores on the MADRS item Unable to Affect and / or the BPRS items Emotional Withdrawal and / or Flat Affect are associated with impaired emotional well-being, social support, and control. Conversely, improvements on the MADRS item Unable to Affect and / or the BPRS items Emotional Withdrawal and Flat Affect are associated with improved emotional well-being, social support, and / or control in maternal functioning, particularly in the BIMF domain of function.

[0496] The inventors conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in social / emotional withdrawal or detachment, in particular reduction or elimination of emotionlessness, emotional withdrawal and / or flat affect.

[0497] The inventors further conclude that reduction or elimination of emotionlessness, emotional withdrawal and / or flat affect by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the MADRS or BPRS total score, but also by an increase in the BIMF score.

[0498] The BIMF total score improves by 10% or more, preferably 20% or more.

[0499] Improvement in maternal function in patients with PPD is reflected by at least an improvement in the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0500] Improvement in maternal function in patients with PPD, as reflected by at least an improvement in BIMF total score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function, as reflected by at least an improvement in BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0501] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, can be administered to patients suffering from PPD, which is associated with social / emotional withdrawal or detachment, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0502] Preferably, patients suffering from PPD associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0503] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms often beginning in the fall and remitting in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0504] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0505] Seasonal affective disorder is associated with social / emotional withdrawal or detachment, including social withdrawal and anhedonia. Seasonal affective disorder is characterized by depressive episodes that meet the criteria for a major depressive episode, including anhedonia, according to the DSM-V.

[0506] Social / emotional withdrawal or detachment in individuals with seasonal affective disorder may be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects of it, can be further assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0507] Patients with seasonal affective disorder have altered resting-state activity involving sensorimotor, attention, and visual processing compared to healthy controls.

[0508] In patients with seasonal affective disorder, altered functional connectivity is observed within and / or between multiple brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Dysfunction in connectivity is observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0509] Treatment of patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, and the associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the seasonal affective disorder.

[0510] In a patient suffering from seasonal affective disorder, the reduction or elimination of social / emotional withdrawal or detachment is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0511] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from seasonal affective disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from seasonal affective disorder 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 pharmaceutically acceptable salt thereof.

[0512] In a patient suffering from seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS inability to have emotions item at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0513] The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," 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 pharmaceutically acceptable salt thereof.

[0514] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the score on the BPRS item "Emotional Withdrawal" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0515] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0516] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on the BPRS item "Flat Affect" at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0517] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with seasonal affective disorder, as reflected by an improvement in the score on the BPRS item "flat affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients with seasonal affective disorder, as reflected by an improvement in the score on the BPRS item "flat affect," 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 pharmaceutically acceptable salt thereof.

[0518] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from seasonal affective disorder is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0519] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from seasonal affective disorder, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in a patient suffering from seasonal affective disorder, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0520] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0521] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from seasonal affective disorder, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from seasonal affective disorder, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0522] Alternatively or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0523] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Trait facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0524] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0525] Reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has abated and extends through the time of assessment.

[0526] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0527] Reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0528] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the mean score for the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0529] In patients with seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Trait, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with seasonal affective disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Domain Detachment, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0530] As mentioned above, social / emotional withdrawal or isolation is closely related to seasonal affective disorder.Therefore, the improvement of social / emotional withdrawal or isolation is also connected to the improvement of seasonal affective disorder.Because social / emotional withdrawal or isolation also affects other aspects of seasonal affective disorder, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of seasonal affective disorder.

[0531] Improvement in seasonal affective disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0532] Improvement in seasonal affective disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S 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 pharmaceutically acceptable salt thereof.

[0533] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, can be administered to patients suffering from seasonal affective disorder, which is associated with social / emotional withdrawal or detachment, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0534] Preferably, patients suffering from seasonal affective disorder associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0535] Persistent depression Persistent depression, also known as dysthymia, is a chronic form of depression. Persistent depression is diagnosed when a person has felt depressed for a large portion of the day, many days, for at least two years. The symptom-free period is less than two months.

[0536] During depression, two or more of the following must be present: 1. Hopelessness; 2. Low energy or fatigue; 3. Low self-esteem; 4. Decreased (insomnia) or increased (hypersomnia) sleep; 5. Loss of appetite or overeating; 6. Difficulty making decisions or poor concentration.

[0537] Patients suffering from persistent depression may suffer from a treatment-resistant form of the disorder.

[0538] According to the DSM-V, persistent depression is characterized by criteria for major depression, including anhedonia, which may be present for two consecutive years. Social withdrawal is also a common symptom in patients with persistent depression.

[0539] Social / emotional withdrawal or detachment in patients with persistent depression may be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects of it, can be further assessed using, for example, the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0540] In patients with persistent depression, altered functional connectivity is observed within and / or between multiple brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Connectivity dysfunction is observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0541] In patients with persistent depression, dysfunctional connectivity and regulation is observed within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0542] Treatment of patients suffering from persistent depression and associated social / emotional withdrawal or detachment, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the persistent depression.

[0543] In patients suffering from persistent depression, the reduction or elimination of social / emotional withdrawal or detachment is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from persistent depression occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from persistent depression 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 pharmaceutically acceptable salt thereof.

[0545] In patients with persistent depression, reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, is reflected by at least an improvement in the score on the MADRS item "inability to have emotions" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients suffering from persistent depression, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, in patients suffering from persistent depression, as reflected by an improvement in the score on the MADRS item "Inability to have emotions," 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 pharmaceutically acceptable salt thereof.

[0547] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from persistent depression is reflected by at least an improvement in the score on the BPRS item "Emotional Withdrawal" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0548] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from persistent depression, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from persistent depression, as reflected by an improvement in the score on the BPRS item "Emotional Withdrawal," 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 pharmaceutically acceptable salt thereof.

[0549] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients suffering from persistent depression is reflected by at least an improvement in the score on the BPRS item "Flat Affect" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0550] The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients suffering from persistent depression, as reflected by an improvement in the score on the BPRS item "flat affect," occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or distancing, particularly flat affect, in patients suffering from persistent depression, as reflected by an improvement in the score on the BPRS item "flat affect," 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 pharmaceutically acceptable salt thereof.

[0551] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depression is reflected by an improvement in the Snaith-Hamilton Psychological Acuity Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0552] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depression, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in patients suffering from persistent depression, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment.

[0553] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depression is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0554] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depression, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from persistent depression, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0555] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depression is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has abated and extends through the time of assessment.

[0556] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0557] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in patients suffering from persistent depression is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0558] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0559] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from persistent depression is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0560] A reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Intimacy Avoidance facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0561] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment in patients with persistent depression is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0562] The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients suffering from persistent depression, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Domain Detachment Feature, 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 pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration having subsided and extending through the time of assessment.

[0563] As mentioned above, social / emotional withdrawal or isolation is closely related to persistent depression.Therefore, the improvement of social / emotional withdrawal or isolation is also connected to the improvement of persistent depression.Because social / emotional withdrawal or isolation also affects other aspects of persistent depression, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of persistent depression.

[0564] Improvement in persistent depression in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0565] Improvement in persistent depression in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in persistent depression in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S 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 pharmaceutically acceptable salt thereof.

[0566] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, can be administered to patients suffering from persistent depression associated with social / emotional withdrawal or detachment, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0567] Preferably, patients suffering from persistent depression associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0568] Anxiety disorders Anxiety disorder is a type of mental health condition. Symptoms include tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety is associated with fear and manifests as a future-oriented mood state that consists of complex cognitive, emotional, physiological, and behavioral response systems related to preparation for anticipated events or situations that are perceived as threatening.

[0569] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0570] Social / emotional withdrawal or detachment, or at least aspects of it, can be assessed using, for example, the Snaith-Hamilton Anhedonia Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0571] Anxiety disorders are associated with alterations in the functional connectivity of resting-state networks. Anxiety disorders exhibit abnormalities in the default mode network (DMN), which influences self-perception, the salience network (SN), which controls emotion / anxiety, and the somatomotor network (SMN), which is responsible for body awareness. The resting-state balance within and / or between these networks, e.g., the SMN and SN, relative to the DMN, may be abnormal in various anxiety disorders.

[0572] Treatment of patients suffering from anxiety disorders and associated social / emotional withdrawal or detachment, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of the anxiety disorder.

[0573] In a patient suffering from an anxiety disorder, reduction or elimination of social / emotional withdrawal or isolation is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0574] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from an anxiety disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from an anxiety disorder 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 pharmaceutically acceptable salt thereof.

[0575] In a patient suffering from an anxiety disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0576] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from an anxiety disorder, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in a patient suffering from an anxiety disorder, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at or after the time the acute hallucinatory experience following the last administration has subsided and extending through the time of assessment.

[0577] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or distancing, particularly anhedonia, in a patient suffering from an anxiety disorder is reflected by at least an improvement in a score on the Dimensional Anhedonia Rating Scale (DARS) about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from an anxiety disorder, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from an anxiety disorder, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0578] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from an anxiety disorder is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0579] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with an anxiety disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from an anxiety disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0580] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from an anxiety disorder is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins after the acute hallucinatory experience following the last administration has subsided and extends through the time of assessment.

[0581] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with an anxiety disorder, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients suffering from an anxiety disorder, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0582] As mentioned above, social / emotional withdrawal or isolation occurs in patients with anxiety disorder.Therefore, the improvement of social / emotional withdrawal or isolation also leads to the improvement of anxiety disorder.Because social / emotional withdrawal or isolation also affects other aspects of anxiety disorder, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of anxiety disorder.

[0583] Improvement in anxiety disorders in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] Improvement in the anxiety disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the anxiety disorder in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S 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 pharmaceutically acceptable salt thereof.

[0585] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry about a wide range of situations and problems. People with GAD may anticipate disasters or be excessively concerned about money, health, family, work, or other issues.

[0586] Generalized anxiety disorder is diagnosed when an individual experiences persistent worry about everyday challenges that is disproportionate to the perceived threat. Patients with GAD typically experience excessive fear that can last for months to years.

[0587] GAD interferes with social, occupational, or other important areas of functioning.

[0588] Patients with GAD may suffer from a treatment-resistant form of the disorder.

[0589] A study of 224 individuals primarily diagnosed with GAD found that anhedonia was an important factor in relation to quality of life (QoL), sleep disturbances, and negative cognitions.

[0590] A large longitudinal study of older adults found that social isolation was associated with increased anxiety and depressive symptoms.

[0591] Social / emotional withdrawal or detachment, or at least aspects of it, can be assessed using, for example, the Snaith-Hamilton Anhedonia Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Inventory for DSM-5 (PID-5) - Adult.

[0592] Patients with GAD exhibit altered functional connectivity, particularly within the default mode network.

[0593] Treating patients suffering from GAD and associated social / emotional withdrawal or detachment, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment, leading to improvement of GAD.

[0594] In a patient with GAD, reduction or elimination of social / emotional withdrawal or estrangement is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0595] The reduction or elimination of social / emotional withdrawal or isolation in a patient with GAD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or isolation in a patient with GAD 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 pharmaceutically acceptable salt thereof.

[0596] In individuals with GAD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, is reflected by an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS) score at least about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment.

[0597] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by at least an improvement in the Snaith-Hamilton Pleasure Scale (SHAPS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS, in patients with GAD, 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 pharmaceutically acceptable salt thereof, with the recall period beginning at the time the acute hallucinatory experience following the last administration subsided and extending through the time of assessment.

[0598] Alternatively or additionally, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with GAD is reflected by an improvement in the score on the Dimensional Anhedonia Rating Scale (DARS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0599] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by at least an improvement in the Dimensional Anhedonia Rating Scale (DARS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment in patients with GAD, as reflected by at least an improvement in the DARS, 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 pharmaceutically acceptable salt thereof.

[0600] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has abated and extends through the time of assessment.

[0601] A reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Anhedonia Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Anhedonia Traits facet, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0602] Alternatively or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with GAD is reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins after the acute hallucinatory experience following the last dose has subsided and extends through the time of assessment.

[0603] A reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with GAD, as reflected by at least an improvement in the mean score on the Personality Inventory for DSM-5 (PID-5)-Adult Withdrawal Traits facet, occurs by approximately 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning after the acute hallucinatory experience following the last dose has subsided and extending through the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with GAD, as reflected by at least an improvement in the mean score on the Personality Inventory of DSM-5 (PID-5)-Adult Withdrawal Traits facet, preferably persists until at least 6 days; particularly until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning after the acute hallucinatory experience following the last administration has abated and extending through the time of assessment.

[0604] As mentioned above, social / emotional withdrawal or isolation occurs in patients with GAD.Therefore, the improvement of social / emotional withdrawal or isolation also leads to the improvement of GAD.Because social / emotional withdrawal or isolation also affects other aspects of GAD, the inventors conclude that the observed improvement of social / emotional withdrawal or isolation also contributes to the overall improvement of GAD.

[0605] Improvement in GAD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0606] Improvement in GAD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in GAD in patients who also suffer from associated social / emotional withdrawal or detachment, as reflected by a reduction in CGI-S 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 pharmaceutically acceptable salt thereof.

[0607] Social anxiety disorder (SAD), also known as social phobia, is one of the most common forms of anxiety. SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations, which can impair school, work, or relationships.

[0608] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations.

[0609] Patients suffering from SAD may suffer from a treatment-resistant form of the disorder.

[0610] Social withdrawal is a core feature of SAD, characterize...

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for treating social / emotional withdrawal or isolation in patients suffering from social / emotional withdrawal or isolation.

2. The pharmaceutical composition according to claim 1, wherein the treatment reduces or eliminates social / emotional withdrawal or isolation.

3. The pharmaceutical composition according to claim 2, wherein the treatment reduces or eliminates pleasure loss, emotional withdrawal, emotional flattening, and / or reduced social engagement.

4. The pharmaceutical composition according to claim 3, wherein the loss of pleasure is measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

5. The pharmaceutical composition according to claim 2, wherein the reduction or disappearance of social / emotional withdrawal or isolation is observed about two hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours; at least seven days; at least fourteen days; and / or at least twenty-eight days.

6. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from a mental or neurological disorder related to social / emotional withdrawal or isolation.

7. The pharmaceutical composition according to claim 6, wherein the patient suffering from a mental or nervous system disorder is suffering from a treatment-resistant form of the disorder.

8. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from a disorder characterized by depressive episodes associated with social / emotional withdrawal or isolation.

9. The pharmaceutical composition according to claim 8, wherein the patient suffering from a disorder characterized by a depressive episode is suffering from a treatment-resistant form of the disorder.

10. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from major depressive disorder (MDD) associated with social / emotional withdrawal or isolation.

11. The pharmaceutical composition according to claim 8, wherein the patient is currently suffering from a major depressive episode.

12. The pharmaceutical composition according to claim 6, wherein the treatment leads to improvement of the diagnosed disorder in a patient who also suffers from related social / emotional withdrawal or isolation.

13. The pharmaceutical composition according to claim 12, in a patient also suffering from associated social / emotional withdrawal or isolation, reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, the improvement of the diagnosed disorder is observed approximately two hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, e.g., approximately 24 hours; at least seven days; at least fourteen days; and / or at least twenty-eight days.

14. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a salt thereof is administered to the patient in a dose or drug regimen that causes the patient to experience a hallucinogenic peak experience.

15. The pharmaceutical composition according to claim 1 or 2, 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.

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

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

18. 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.

19. The pharmaceutical composition according to claim 18, wherein each subsequent dose is administered in a larger amount than the previous dose.

20. The pharmaceutical composition according to claim 18, wherein the patient is administered a subsequent dose unless he or she experiences a hallucinogenic euphoria.

21. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT is administered in a dose of approximately 2 mg to approximately 8 mg for a first dose, then increased to a dose of approximately 8 mg to approximately 14 mg for a second dose, unless the patient has not yet experienced a hallucinogenic peak experience or the attending physician determines that further dose increases are inappropriate based on observed side effects, then increased to a dose of approximately 14 mg to approximately 20 mg for a third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered.

22. The pharmaceutical composition according to claim 21, wherein a first dose of 5-MeO-DMT is about 6 mg, a second dose of 5-MeO-DMT is about 12 mg, a third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered.

23. The pharmaceutical composition according to claim 18, 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.

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

25. The pharmaceutical composition according to claim or 2, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by inhalation, or by nasal administration, buccal administration, or sublingual administration.