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 in the treatment of patients suffering from social / emotional withdrawal or isolation, and the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous routes.

Description

[Technical Field]

[0001] The present invention relates to disorders characterized by social / emotional withdrawal or detachment, in particular depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder; anxiety disorders, 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, such as chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as For example, improved methods are directed to treating social / emotional withdrawal or isolation in patients suffering from psychiatric or nervous system disorders such as substance use disorders (SUDs); psychotic disorders, e.g., schizophrenia; dementia, e.g., 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, e.g., 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 may also occur in patients suffering from medical health conditions that lead to associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

[0004] The 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 lumped together 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. Patients suffer from anhedonia when they have a subjectively reduced ability to experience pleasure in everyday activities. Anhedonia contains a consummatory (or preferential) and an anticipatory (or wanting) component. Consummatory pleasure refers to the "in-the-moment" pleasure experienced by a subject directly involved in a pleasurable activity, whereas 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 diminished intensity or range of feelings or emotions.

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

[0010] Social / emotional withdrawal or isolation can not only have a significant impact on quality of life, but can also lead to a variety of secondary health problems.

[0011] Thus, there is a need for improved methods for treating social / emotional withdrawal or isolation, particularly social / emotional withdrawal or isolation 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 (i.e., a) have a greater percentage of patients experiencing a clinical response, b) have a greater mean clinical response, c) have a more rapid onset of clinical response, and / or d) have a more durable clinical response) than previously described therapies.

[0013] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens that have a superior 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 that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens 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 aspects and specific disease subgroups 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 patients 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 disorders characterized by social / emotional withdrawal or detachment, in particular depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder; anxiety disorders, 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, such as chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as Improved methods are provided for treating social / emotional withdrawal or isolation in patients suffering from psychiatric or nervous system disorders such as substance use disorders (SUDs); psychotic disorders, e.g., schizophrenia; dementia, e.g., Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorders (ASDs); attention deficit hyperactivity disorder (ADHD); and personality disorders, e.g., 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 isolation in patients suffering from medical health conditions leading to associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

[0018] The present invention also provides dose ranges and regimens useful for treating social / emotional withdrawal or distancing, particularly anhedonia, emotional withdrawal, flat affect and / or decreased social interaction.

[0019] In the context of the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous administration.

[0020] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that induces a hallucinogenic high in the patient. A dose of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt thereof may be administered. DETAILED DESCRIPTION OF THE INVENTION

[0021] 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.

[0022] As used in the context of the present invention, a "patient" to be treated is a human subject who is identified by a licensed professional and in accordance with accepted medical practice as suffering from social / emotional withdrawal or estrangement, or who has been diagnosed by a licensed professional and in accordance with accepted medical practice as having a psychiatric or neurological disorder associated with social / emotional withdrawal or estrangement, in which case the assessment of social / emotional withdrawal or estrangement may or may not be part of the diagnosis.

[0023] Diagnosis of a mental or nervous system disorder may be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will become apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or patient groups that would particularly benefit from treatment according to the present invention. In any event, the diagnosis is made by a physician or psychologist. It is not sufficient that the human subject themselves believe that they are suffering from the disorder.

[0024] 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.

[0025] "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 practices of methods according to the present invention to alleviate the signs and / or symptoms of, or to eliminate, social / emotional withdrawal or isolation.

[0026] The social / emotional withdrawal or isolation may be associated with a sleep disorder, such as insomnia, a psychiatric or nervous system disorder, or another medical condition.

[0027] 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.These at least two previous treatment courses are particularly administered during the current disease episode, for example, when patient suffers from a disorder characterized by depressive episode, during the current depressive episode.

[0028] As used in the context of this invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of 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.

[0029] "Clinical response" includes, but is not limited to, improvements on rating scales assessing (i) social / emotional withdrawal or detachment or aspects of social / emotional withdrawal or detachment, and / or (ii) psychiatric or neurological disorder or aspects of such disorder, and / or (iii) medical health conditions leading to the associated psychiatric or neurological disorder, and / or (iv) sleep.

[0030] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, a measure of symptom severity, response to treatment, and efficacy of treatment.

[0031] The CGI rating scale was developed to provide a brief, independent assessment of a clinician's view of a patient's overall functioning before and after treatment (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0032] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of mental illness in this patient?" This is rated on a 7-point scale: 1 = normal (no illness), 2 = borderline mental illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = patient with very severe illness.

[0033] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0034] 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 score of at least one level. Preferably, the CGI-S score is decreased by at least two levels and / or to a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three levels and / or to a score of 0.

[0035] 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 drug treatment began), 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."

[0036] 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).

[0037] 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 aspects of the disease.

[0038] 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. The active compound may be administered intravenously, intramuscularly, or subcutaneously.

[0039] 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 "dosage regimen" (or "dosage regimen") shall mean the prescribed sequence of one or more individual administrations.

[0040] Social / emotional withdrawal or isolation Symptoms such as anhedonia, emotional withdrawal, and flat affect are lumped together herein as social / emotional withdrawal or isolation. Decreased social engagement is a further aspect associated with social / emotional withdrawal or isolation.

[0041] Anhedonia is the inability to experience pleasure. Patients do not suffer from anhedonia if they have no subjective reduction in their ability to experience pleasure in everyday activities. Anhedonia can be mild, where pleasure from usual pleasurable activities is slightly reduced; moderate, where pleasure from usual pleasurable activities is significantly reduced or some pleasure from isolated activities is maintained; or severe, where pleasure is completely incapable of being experienced.

[0042] Anhedonia contains consummatory (or liking) and anticipatory (or wanting) components. Consummatory pleasure refers to the "in the moment" pleasure experienced by a subject directly involved in an enjoyable activity, whereas anticipatory pleasure refers to the experience of pleasure related to a future activity.

[0043] Flat affect is characterized by a subjective sensation of a decrease in the intensity or range of emotions or feelings. A subject does not exhibit flat affect if they do not perceive a decrease in the intensity or range of emotions or feelings. Flat affect is mild when there is a slight contraction in the range of emotions or a transient decrease in the range or intensity of emotions; moderate when there is a significant contraction in the range or intensity of emotions, but some emotions are preserved (e.g., an inability to cry); and severe when there is a significant and comprehensive contraction in the range of emotions or an inability to experience normal emotions.

[0044] Emotional withdrawal or detachment is the inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item regarding emotional withdrawal, which is characterized as a subject's lack of ability to emotionally engage in an interview situation. According to this BPRS item description, emotional withdrawal is absent if the subject spontaneously engages with the interviewer most of the time, without a lack of emotional engagement indicated by occasional lack of response, occasional distraction, or awkward smiling. A mild form of emotional withdrawal is present if there is a lack of emotional engagement indicated by a noticeable lack of response, distraction, or lack of warmth, but the subject responds to the interviewer when prodded. Emotional withdrawal is moderate if emotional contact is absent for the majority of the interview, due to the subject's apathetic responses, lack of eye contact, not seeming to care whether the interviewer is listening, or possibly being distracted by psychopathic content. Additionally, emotional withdrawal is moderately severe when emotional contact is absent for the majority of the interview. Severe forms exist when the subject actively avoids emotional engagement, or when the subject is often unresponsive, responds with yes / no questions, or responds with minimal emotion. Emotional withdrawal is most severe when the subject consistently avoids emotional engagement, unresponsive, responds with yes / no questions, or sometimes leaves during the interview or does not respond at all.

[0045] Decreased social engagement characterizes subjective reports of decreased social and interpersonal engagement or interaction. Absence of reports of decreased social and interpersonal engagement or interaction indicates absence of decreased social engagement. Decreased social engagement can be mild, where social engagement is slightly decreased but without impairment of social and interpersonal functioning; moderate, where social engagement is clearly decreased with some functional sequelae (e.g., avoidance of some social engagement or conversation); or severe, where social interaction is significantly reduced or where almost all forms of social contact are avoided (e.g., refusing to answer the phone or meet with friends or family).

[0046] Social / emotional withdrawal or isolation may be associated with a psychiatric or neurological disorder, or some other medical condition.

[0047] Mental or nervous system disorders leading to or associated with social / emotional withdrawal or detachment include disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, 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., PTSD; These include 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); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0048] Social / emotional withdrawal or isolation can also occur in patients suffering from sleep disorders, such as insomnia.

[0049] Social / emotional withdrawal or estrangement can also occur in patients suffering from medical health conditions that lead to associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

[0050] Measuring social / emotional withdrawal or distancing Social / emotional withdrawal or detachment or its individual aspects (such as anhedonia, emotional withdrawal, and flat affect) can be assessed by different means such as questionnaires or scales.

[0051] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the physician administering the questionnaire. Questionnaires used to assess whether a patient has a specific psychiatric or neurological disorder may include items related to social / emotional withdrawal or estrangement.

[0052] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale measuring anhedonia, or the inability to experience pleasure. Items address the areas of social interaction, food and drink, sensory experiences, and interests / recreation. A score of 2 or less is considered "normal," while an "abnormal" score is defined as 3 or greater. Each item allows for a four-point response: strongly disagree, disagree, agree, or strongly agree. Any "disagree" response receives a score of 1, and any "agree" response receives a score of 0. Thus, the final score ranges from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. While the SHAPS has been used to measure anhedonia in depression, it is also frequently used to assess anhedonia in other patient populations.

[0053] In principle, SHAPS measures hedonic tone over the past few days with 14 hypothetical items. However, due to the hypothetical nature of the items, shorter recall periods appropriate for earlier assessment time points may also be applied.

[0054] Alternatively or additionally, anhedonia can be assessed using the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort, and consummatory pleasure across four domains: hobbies, food / drinks, social activities, and sensory experiences. The DARS contains 17 items assessing current anhedonia states. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all true) to 4 (very true), with higher scores indicating lower anhedonia. All items are summed to obtain a total score ranging from 0 to 68. For each of the four hedonic domains—hobbies (4 items, total score 0–16), food / drinks (4 items, total score 0–16), social activities (4 items, total score 0–16), and sensory experiences (5 items, total score 0–20)—participants are asked to provide two or three examples of their own preferences.

[0055] The Personality Disorders Assessment for DSM-5 (PID-5) - Adult is a 220-item self-rating personality trait scale for adults aged 18 years and older. The PID-5 assesses 25 personality trait facets, each consisting of 4 to 14 items, including anhedonia, anxiety, attention-seeking behavior, callousness, cunningness, depression, distractibility, eccentricity, emotional lability, grandiosity, hostility, impulsivity, avoidance of intimacy, irresponsibility, manipulativeness, perceptual dysregulation, perseveration, emotional restriction, rigid perfectionism, risk-taking, separation anxiety, submissiveness, suspiciousness, unusual beliefs and experiences, and social withdrawal.

[0056] The trait facet of anhedonia includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (devalued items are marked with the letter "R"), the trait facet of withdrawal includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186, and the trait facet of intimacy avoidance includes items 89, 97R, 108, 120, 145, and 203. These three trait facets can be combined to obtain a broader trait domain labeled estrangement.

[0057] The measure is completed by individuals before meeting with a physician. Each item asks individuals to rate how well the item describes them generally.

[0058] Each item in this measure is rated on a four-point scale. Item response categories are: 0 = very wrong or often wrong; 1 = sometimes or somewhat wrong; 2 = sometimes or somewhat correct; and 3 = very correct or often correct. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, the items are reversed before being entered into the scale score calculation.

[0059] Scores for items within each trait facet should be summed and entered into the appropriate raw facet score box. In addition, clinicians are asked to calculate and use an average score for each facet and domain. The average score allows clinicians to assess an individual's personality disorder against observed norms by converting the overall score and scores for each domain onto a four-point scale. The average facet score is calculated by dividing the raw facet score by the number of items in the facet (e.g., if all items in the "anhedonia" facet are rated as "sometimes or somewhat true," the average facet score would be 16 / 8 = 2 (indicating moderate anhedonia)). The average domain score is calculated by summing the three facet scores that primarily contribute to that particular domain and then averaging them. For example, if the average facet scores for anhedonia, intimacy avoidance, and withdrawal (a measure primarily indicative of detachment) were all 2, the sum of these scores would be 6, and the average domain score would be 6 / 3 = 2. Higher mean scores indicate greater impairment in a particular personality trait facet or domain.

[0060] High scores in facets or domains may indicate salient and problematic areas for the individual receiving care, which may warrant further evaluation, treatment, and follow-up.

[0061] Scales for assessing mental and nervous system disorders A number of scales have been suggested for assessing the severity of psychiatric or neurological disorders, which are based on tests that can be self-administered or administered by a physician.

[0062] Scales that may be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0063] Treatment outcome is assessed at one or more time points after the course of treatment is completed by using one or more indicators or measures.

[0064] 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 assessments can generally be performed, for example, about 2 hours or about 3 hours after the last dose.

[0065] However, assessment of the effect on sleep disorders can be performed as early as the day after treatment (ie, Day 1) so that the treated patient has had an opportunity to sleep for at least one night.

[0066] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. This 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. This evaluation can occur after about 24 hours.

[0067] Assessment on day 7 or assessment at day 7 means assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0068] Based on the endpoint that is designed for a longer recall period (for example, MADRS is usually 7 days), for example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response at an early time point (for example, 2 hours) after drug administration, reasonable modification of such endpoint can be applied (for example, change the recall period of MADRS to 2 hours, and carry forward the sleep item recorded at the baseline before drug administration).Unless recall period is specifically indicated, the same applies to any other scale that is applied herein.

[0069] At earlier time points, the outlined considerations 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.

[0070] At later time points (e.g., after Day 1), all items on the relevant scales for assessing clinical response can usually be assessed, with the recall period adapted as necessary so that no pretreatment scores need to be carried forward.

[0071] Resting networks and social / emotional withdrawal or isolation Brain processing can be studied by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0072] Functional brain images are acquired over several minutes. Low-frequency BOLD signal amplitude patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distribution areas with correlated and anti-correlated fluctuations.

[0073] In this way, resting-state fMRI can 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 overt cognitive task (i.e., at rest). The observed patterns characterize networks of brain regions with consistent patterns of signal fluctuations, and are referred to as resting-state networks (RSNs).

[0074] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the activation patterns seen in resting-state networks and task-based fMRI experiments.

[0075] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, and resting-state networks have been characterized with respect to aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0076] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various disease states. Such disease states, including certain forms of social / emotional withdrawal or isolation, are associated with altered functional connectivity between one or more regions within a specific resting-state network and / or in one or more additional resting-state networks.

[0077] Alterations in RSNs are also involved in anhedonia, a key aspect of social / emotional withdrawal or detachment. 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, salience, DAN, somatomotor, and visual networks.

[0078] Additionally, emotional detachment in adult psychopathy has been associated with structural abnormalities in the dorsal DMN. The dorsal DMN is of particular interest in the development of psychopathy due to its functions associated with psychopathy. Specifically, the dorsal DMN and the regions it connects to (the medial prefrontal cortex and posterior cingulate cortex (PCC)) support emotional, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN have been associated with the emotional and interpersonal differences that define this disorder.

[0079] Thus, patients suffering from social / emotional withdrawal or estrangement exhibit altered functional connectivity within and / or between RSNs when compared to healthy age-matched controls. Alterations are observed within and / or between the DMN, salience, DAN, somatomotor, and visual networks.

[0080] In many cases, RSNs involved in social / emotional withdrawal or detachment are associated with disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, 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, such as chronic pain and fibromuscular atrophy. Pain; mental and behavioral disorders due to psychoactive substance use, e.g., substance use disorder (SUD); psychotic disorders, e.g., schizophrenia; dementia, e.g., 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, e.g., schizotypal personality disorder and borderline personality disorder (BPD).

[0081] Resting-state networks involved in social / emotional withdrawal or distancing are also affected by psychiatric or neurological disorders that are the result of certain medical health conditions, such as traumatic brain injury (TBI).

[0082] Resting-state networks involved in social / emotional withdrawal or isolation are also affected by sleep disorders, such as insomnia. Indeed, there is a correlation between social / emotional withdrawal or isolation and disturbances in sleep.

[0083] Treatment of social / emotional withdrawal or isolation and psychiatric or neurological disorders The present invention can treat social / emotional withdrawal or isolation that occurs in patients suffering from psychiatric or nervous system disorders, and can also treat social / emotional withdrawal or isolation that occurs in patients suffering from sleep disorders, such as insomnia.

[0084] In patients suffering from social / emotional withdrawal or isolation associated with another condition, such as those detailed above, treatment of the social / emotional withdrawal or isolation according to the present invention results in an improvement in the condition associated with the social / emotional withdrawal or isolation.

[0085] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0086] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathological, inappropriately connected connections as the networks reconnect. New, healthy functional connectivity is established, resulting in lasting benefits.

[0087] Thus, in accordance with the present invention, affecting these networks by therapies as described herein will result in an improvement in social / emotional withdrawal or isolation, and, if the patient being treated suffers from a psychiatric or nervous system disorder, also result in an improvement in the disorder, and, if the patient being treated suffers from a sleep disorder, such as insomnia, also result in an improvement in the sleep disorder, such as insomnia.

[0088] 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 and observed specific improvements in social / emotional withdrawal or detachment that are also typically observed in patients with other disorders.

[0089] This data comes 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, the inventors have determined that certain clinical findings from the study may be relevant to devising treatments for other conditions associated with social / emotional withdrawal or isolation, as discussed in detail below.

[0090] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are the group that received a single dose of 12 mg and the group that received an individualized daily dose schedule (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0091] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the study was to demonstrate treatment efficacy through improvement in overall MADRS scores, the inventors focused on items included in various scales and found that specific subscore items, such as those related to social / emotional withdrawal or detachment, may be relevant to other conditions in which social / emotional withdrawal or detachment is based on similar changes in functional connectivity within and / or between the default mode network, salience, dorsal attention, somatomotor, and visual networks.

[0092] 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.

[0093] More specifically, the aspect that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or isolation, particularly anhedonia, emotional withdrawal, and / or flat affect. Another aspect that can be treated is reduced social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate social / emotional withdrawal or isolation, particularly anhedonia, emotional withdrawal, and / or flat affect, in the patient. In addition, reduced social engagement is improved, i.e., reduced or eliminated.

[0094] Of particular relevance to social / emotional withdrawal or detachment, the MADRS "Inability to Have Emotions" scale items describe the subjective experience of diminished interest in one's surroundings or in activities that usually bring pleasure. A diminished ability to respond emotionally appropriately to situations and people.

[0095] A score of 0 indicates normal interest in surroundings and others, 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 experiencing emotional numbness, an inability to feel anger, deep sadness, or joy, and a complete or distressing inability to care for close relatives and friends.

[0096] In the study group receiving the individualized dosing plan, the combined MADRS "Inability to Have Emotions" item score across all eight patients 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.

[0097] In the 12 mg group, the combined MADRS "Inability to Have Emotions" item score across all four patients had a baseline of 16. After two hours, the score decreased to 9, corresponding to a 7-point or 44% improvement. On day 1 after treatment, the score decreased to 1, corresponding to a 15-point or 94% improvement. On day 7 after treatment, the score decreased to 1, corresponding to a 15-point or 94% improvement.

[0098] BPRS scale items that are particularly relevant to social / emotional withdrawal or detachment are "inability to have emotions" and "affective blunting."

[0099] The BPRS "emotional withdrawal" item concerns the patient's lack of ability to engage emotionally in interview situations. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. Lack of emotional engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but the individual engages spontaneously 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 the majority of the interview, as the subject is short-spoken, avoids eye contact, does not seem to care if the interviewer is listening, or may be distracted by psychotic content. 5 - Moderately severe. Similar to '4', but emotional contact is absent for the majority of the interview. 6 - Severe. Actively avoids emotional involvement. Often unresponsive or responds with yes / no responses (not solely due to paranoia). Responds with minimal emotion. 7 - Most severe. Consistently avoids emotional involvement. Unresponsive or yes / no responses (not solely due to paranoia). May leave during the interview or not respond at all.

[0100] The BPRS "emotional withdrawal" item score was compiled with a baseline of 13. After 3 hours, the score decreased to 8, which corresponds to a 5-point or 38% improvement. After 1 day of treatment, the score decreased to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, the score decreased to 8, which corresponds to a 5-point or 38% improvement.

[0101] In the 12 mg group, the baseline score for the BPRS "emotional withdrawal" item was 13. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. On the first post-treatment day, the score decreased to 8, corresponding to a 5-point or 38% improvement. On the seventh post-treatment day, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0102] The BPRS "blunted affect" item concerns a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness, even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2 - Very mild. Emotional range is somewhat muted or subdued, but facial expression and vocal tone are within the normal range and appropriate. 3 - Mild. Overall range of emotion is muted, suppressed, or subdued, with few spontaneous and appropriate emotional responses. 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. Expressive or gesticulating emotions usually return to a flat affect. 5 - Moderately severe. Emotional range is extremely diminished; 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 constant. Voice tone is monotonous most of the time. 7 - Most severe. Virtually no emotional range or expression, stiff movements, and a persistently monotonous tone of voice.

[0103] Scores for the BPRS "blunted affect" item 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.

[0104] In the 12 mg group, the baseline score for the BPRS "blunted affect" item was 11. After 3 hours, the score had decreased to 8, corresponding to a 3-point or 27% improvement. On the first post-treatment day, the score had decreased to 6, corresponding to a 5-point or 45% improvement. On the seventh post-treatment day, the score had decreased to 5, corresponding to a 6-point or 55% improvement.

[0105] Thus, scores on scales particularly relevant to social / emotional withdrawal or detachment, i.e., "unable to have emotions" (MADRS), "emotional withdrawal" (BPRS), and "blunted 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 in patients who also suffer from a psychiatric or nervous system disorder, or a sleep disorder, such as insomnia.

[0106] As a result, according to 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.

[0107] Active Agent The above discussion indicates that social / emotional withdrawal or estrangement represents a significant disease burden in itself and deserves appropriate treatment.

[0108] The inventors reasoned that carefully selected hallucinogens may improve the treatment of important aspects of social / emotional withdrawal or isolation and improve the condition overall.

[0109] 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.

[0110] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0111] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and minor amine-associated receptors.

[0112] 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.

[0113] 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 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a self-reported manic episode after ingesting psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0114] 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.

[0115] 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 to be administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0116] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for use in therapy. 5-MeO-DMT has a unique pharmacological profile that differs from the pharmacological profiles of other hallucinogenic compounds.

[0117] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0118] 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 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. Thus, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe agonist activity (p<0.05) is 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / high affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0119] 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 have an increased contribution to 5-HT2A binding compared to 5-MeO-DMT, with the latter exhibiting the greatest difference in affinity for 5-HT1A over 5-HT2A of the three compounds. Therefore, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effect of 5-MeO-DMT compared to the other two compounds.

[0120] 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 being associated with mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0121] 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 nervous system disorders, including disorders characterized by depressive episodes (e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD) (e.g., bipolar I disorder and bipolar II disorder), psychotic disorders (e.g., schizophrenia), or personality disorders (e.g., schizotypal personality disorder)). Patients suffering from such psychiatric or nervous system disorders do not experience treatment-emergent mania or hypomania when treated in accordance with the present invention.

[0122] 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).

[0123] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0124] 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.

[0125] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as a "loss of self"), often leading 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 intravenous injection, 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 changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0126] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have investigated the efficacy of 5-MeO-DMT against recombinant human 5-HT7 receptors and their receptors as radioligands. 3 Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM.

[0127] Thus, in addition to the 5-HT1A and 5-HT2A receptors described above, 5-MeO-DMT also interacts with the 5-HT7 receptor, at which it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0128] 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.

[0129] 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.

[0130] 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. In patients with sleep disorders, analysis of resting-state functional connectivity has revealed altered functional connectivity between the SNU and regions within the default mode network.

[0131] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe this may allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0132] 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.

[0133] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, in addition to the 5-HT1A receptor, as two mediators of the effects of 5-MeO-DMT, including "resetting" functional network connectivity and neuroplasticity, may also enable it to exert beneficial effects in patients suffering from other conditions or symptoms, 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.

[0134] Another characteristic of 5-MeO-DMT is its short half-life.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] The properties of 5-MeO-DMT make the compound particularly suitable for treating social / emotional withdrawal or isolation, especially in patients suffering from psychiatric or neurological disorders.

[0139] The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

[0140] 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.

[0141] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0142] 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.

[0143] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0144] 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.

[0145] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Still further examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. It should be noted that combinations of the above substitution patterns are also contemplated.

[0146] Methods for preparing these compounds are known in the art.

[0147] 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.

[0148] 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.

[0149] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be 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 with a 5-MeO-DMT prodrug or a salt thereof.

[0150] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0151] An example of a suitable organic moiety is —C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 where R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0152] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 where R 1 , R 3 , and R 4 is defined as above.

[0153] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0154] 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).

[0155] Methods for preparing the prodrugs described herein are known in the art.

[0156] 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.

[0157] 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.

[0158] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenously, i.e., by intravenous injection.

[0159] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration via injection; examples of excipients and vehicles for such formulations are known in the art.

[0160] Dosage regimen The present invention also provides dosage ranges, specific dosages, as well as administration regimens (administration schemes) and suitable routes of administration.

[0161] The present invention is based in part on the inventors' conclusion that the manifestation of an acute hallucinogenic peak experience 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 or a pharmaceutically acceptable salt thereof in patients suffering from social / emotional withdrawal or detachment, particularly one or more of the aspects defined above.

[0162] The result is a superior therapeutic profile, achieving peak experiences more rapidly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens, dosing regimens, and routes of administration.

[0163] 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 meaningless hallucinogenic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, starting with a low dose allows patients to become accustomed to the hallucinogenic experience in general and prepare them for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at such higher doses. 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.

[0164] 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.

[0165] Patients, as defined herein, who suffer from social / emotional withdrawal or isolation are treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0166] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for social / emotional withdrawal or isolation).

[0167] The dosage of 5-MeO-DMT administered to a patient, as defined herein, suffering from social / emotional withdrawal or isolation, ranges from about 1 mg to about 10 mg, or any amount within that range, and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT (e.g., the hydrobromide salt), the weight of which can be calculated from the stated weight of the 5-MeO-DMT free base, assuming equimolar amounts are used. Specific useful amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. It should be noted that when a range such as "about 1 mg to about 10 mg" is indicated herein, the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0168] 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 a clinical response occurring by about 2 hours after administration of 5-MeO-DMT.

[0169] 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 a clinical response (including a clinical response occurring by about 2 hours after administration of 5-MeO-DMT) that is sustained 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.

[0170] 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 administering more than one dose of 5-MeO-DMT.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] In certain embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0175] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0176] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0177] For embodiments in which the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration will be 7 mg.

[0178] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration and to a dosage selected from about 7 mg to about 9 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 amounts useful for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0179] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and to a dosage selected from about 2.5 mg to about 3.5 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 amounts useful for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0180] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 10 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 an 8 mg dose, and therefore the highest dosage in the first treatment block is 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.

[0181] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic 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 useful for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0182] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic 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 useful for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0183] It is preferred that a pharmaceutically acceptable salt of 5-MeO-DMT be used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0184] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0185] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Mystical Experiences Questionnaire-Revised (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0186] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Feeling (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0187] In accordance with the present invention, the occurrence of a "Peak Hallucinatory Experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) total score (also called the Peak Hallucinatory Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control did it make you feel? 3. How profound (i.e., meaningful) was the experience?

[0188] Treating social / emotional withdrawal or isolation and sleep disorders A sleep disorder is a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition, such as a psychiatric or neurological 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.

[0189] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. NREM sleep can be divided into four stages (I-IV). These NREM stages correspond to increasing depths of sleep. NREM and REM sleep alternate during each of the four to five normal human sleep cycles each night. During the earlier hours of the night, NREM sleep is deeper and occupies a disproportionately large portion of the time, especially within the first sleep cycle. As the night progresses, NREM sleep becomes shallower, with a greater proportion of each cycle being allocated to REM sleep.

[0190] Normal, healthy sleep consists of different phases, as outlined above, which progress in a continuous and strictly controlled sequence throughout the night.

[0191] When this tight control is disrupted, sleep disorders occur.

[0192] Common forms of sleep disorders include problems falling asleep and maintaining sleep (insomnia), excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), disorders related to sleep, sleep stages, or incomplete awakening (parasomnia), 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.

[0193] Insomnia is a sleep disorder that causes people to have 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; not feeling like they've slept enough; and / or have at least one problem during the day due to lack of sleep, such as fatigue, sleepiness, mood, problems concentrating, or accidents at work or while driving.

[0194] 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 is a difficulty in transitioning from sleep to wakefulness. Individuals experiencing sleep drunkenness report confusion, disorientation, and sluggishness upon awakening, and repeatedly returning to sleep.

[0195] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances due to alterations in an individual's internal circadian rhythm or misalignment between an individual's circadian rhythm and the desired or required schedules of work or society. This dyssynchrony can be transient or persistent. The resulting clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and interrupted, performance during desired wakefulness is impaired, and temporary attempts to return to a regular sleep schedule are unsuccessful.

[0196] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavior or physiological activity (such as sleepwalking or nightmares) that people experience before falling asleep, during sleep, or during periods of arousal between sleep and wakefulness. They vary considerably in nature, severity, and frequency. Parasomnias can reduce the quality of sleep.

[0197] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated activity of respiratory muscles and the brain. With potentially serious effects on sleep and blood oxygen and carbon dioxide balance, these sleep disorders manifest as chronic snoring, sleep apnea, sleep-related hypoventilation, and / or hypoxemia. In some of these disorders, breathing is abnormal even during waking hours. Reduced airflow leads to intermittent hypoxia with microarousals or awakenings, causing sleep fragmentation and excessive daytime sleepiness. The resulting inflammation and endothelial dysfunction can place individuals at risk for atherosclerosis by reducing vascular elasticity and increasing clotting, which, along with reduced oxygenation, can cause heart and brain damage.

[0198] In sleep-related movement disorders, relatively simple, usually stereotyped, repetitive movements interfere with sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0199] Fatigue describes a tired state that is not relieved by rest or sleep. Fatigue is usually experienced as a weakening or depletion of an individual's physical or mental resources and is a feeling of extreme tiredness, lethargy, or low energy characterized by a decreased ability to work and a decreased efficiency in responding to stimuli. Fatigue is common after periods of mental or physical exertion, but can sometimes occur in the absence of such exertion as a symptom of an ill health.

[0200] Not getting adequate sleep quantity or quality can lead to personality changes, exacerbate existing mental disorders, and even precipitate the onset of new ones. Sleep disorders can also lead to social withdrawal, as lack of sleep leads to increased loneliness and a decreased willingness to socialize. 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 also negatively impact a person's life by contributing to the development of obesity, diabetes, and heart disease.

[0201] Treatment for sleep disorders varies depending on the 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.

[0202] Available treatments are not effective in all patients, may be associated with side effects, and / or may require long-term treatment to achieve adequate therapeutic benefit.

[0203] In patients suffering from a sleep disorder associated with a psychiatric or nervous system disorder, known treatments for the psychiatric or nervous system disorder do not always improve the sleep disorder.

[0204] For example, sleep disorders are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of the associated sleep disorders. Most antidepressants have been shown to affect sleep architecture, and while some antidepressant classes improve sleep, 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).

[0205] To assess sleep, parameters such as sleep duration, sleep architecture, sleep latency, and wake frequency and duration throughout the night can be measured. Quantitative metrics may be measured using objective methods, including polysomnography, actigraphy, and sleep latency assessment, or by self-report measures (questionnaires).

[0206] Polysomnography is a technique that involves overnight monitoring of a patient in a specialized clinical facility. Various functions are measured throughout the night, including eye movement, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0207] Sleep latency can be measured by multiple sleep latency testing (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep over multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal, while a mean sleep latency of less than 8 minutes indicates a sleep disorder. Analysis of accompanying brain activity can further aid in the diagnosis of sleep disorders.

[0208] The sleep assessment questionnaire captures assessment of components of sleep quality such as depth of sleep, difficulty waking up, and perception of soundness of sleep, in addition to other factors that may affect sleep quality such as comorbidities and medication use.

[0209] Assessment of qualitative aspects of the sleep experience is important because sleep dissatisfaction can often persist despite normal quantitative measures of sleep.

[0210] Not only do questionnaires facilitate the rapid and accurate assessment of complex clinical problems, but they can also be useful in tracking patient progress. Self-reported sleep questionnaires completed by patients are therefore an important pillar for the assessment of sleep disorders in clinical practice.

[0211] Various sleep quality indices are known. The following indices each include examples of questionnaires for assessing sleep overall, and for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias in particular. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0212] Sleep quality can generally be assessed, for example, by the Sleep Quality Scale (SQS) and the Sleep-50 questionnaire.

[0213] The Sleep Quality Scale (SQS) is a comprehensive assessment tool for achieving a general and efficient measure suitable for assessing sleep quality in various patient and research populations. Individual questions about daytime symptoms such as attention, concentration, or memory problems (item 15, "Lack of sleep makes it hard to think," item 19, "Lack of sleep makes me make mistakes at work," item 21, "Lack of sleep makes me forgetful," item 22, "Lack of sleep makes it hard to concentrate at work"), recovery after sleep, problems falling asleep and staying asleep, difficulty waking up, and sleep satisfaction can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more severe sleep problems.

[0214] The SLEEP-50 questionnaire consists of 50 items designed to screen for various types of sleep disorders in the general population. The scale consists of nine subscales reflecting some of the most common sleep-related disorders and complaints, as well as factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic limb 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 asked to indicate how well the statement matches their experience over the past month or another appropriate recall period, using a scale ranging from 1 ("not at all true") to 4 ("very true").

[0215] The questionnaire requires that not only certain subscales (e.g., insomnia) exceed certain cutoff points for the diagnosis of a sleep disorder, but also the impact of the subscales (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46., table 4 for optimal cutoff points and scoring procedures).

[0216] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0217] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other instruments are the Insomnia Severity Index and the Espie Sleep Disorders Questionnaire.

[0218] 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 specific sleep difficulties over the past month or another suitable recall period.

[0219] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0220] Each component is assigned a score of 0 to 3. Higher scores indicate more severe sleep disturbances. Details of how the Pittsburgh Sleep Quality Index is scored can be found in the appendix to Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0221] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21 points, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. The cutoff for the overall score is 5, which distinguishes between those with and without sleep problems. A total score >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0222] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a reduction in score, preferably (ii) to 5 or less.

[0223] The Insomnia Severity Index (ISI) is a five-item questionnaire regarding 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 function at work / daily chores, concentration, memory, mood, etc.)?"), how noticeable the respondent feels their insomnia is compared to others, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (= none) to 4 (= very), with higher total scores corresponding 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).

[0224] The typical recall period for an ISI is two weeks, although other suitable recall periods may also be used herein.

[0225] Successful treatment is indicated by (i) a reduction in score (eg, >7 points, especially >8 points), and preferably (ii) a reduction below the cut-off for clinically significant insomnia.

[0226] 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 disturbances, a growing body of research suggests that daytime beliefs about sleep may be equally important in the insomnia experience. The SPS items assess two distinct domains: cognitive and behavioral consequences of sleep deprivation (e.g., negative thoughts and perceptions), and emotional consequences (e.g., worry and distress). This tool may be particularly useful for clinicians attempting to identify and treat the causes of sleep problems in patients.

[0227] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. With assessments of restlessness / agitation, mental overreactivity, consequences of insomnia, and poor sleep readiness, the SDQ specifically addresses beliefs about the source of sleep problems. Respondents use a 5-point scale to indicate how frequently certain statements about insomnia describe their experience. 1 means "never true," while 5 means "very often 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).

[0228] Treatment success is indicated by a decrease in score.

[0229] Hypersomnolence or hypersomnolence can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0230] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations that represent periods of relative inactivity (e.g., an afternoon nap or being stuck in a car in traffic). Using a scale of 0 to 3 (0 meaning "very unlikely to fall asleep" and 3 meaning "very likely to fall asleep"), 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 potentially clinically significant levels of daytime sleepiness (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).

[0231] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0232] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment. The scale consists of a single item and asks respondents to select one of seven statements that best describes their current level of sleepiness. A scale ranging from 1 (=motivated, active, alert, not sleepy) to 7 (=drowsy, unable to stay awake, likely to fall asleep) is used to assess sleepiness (A. Shahid et al., loc. cit., Hoddes et al., The development and use of the Stanford sleepiness scale (SSS). Psychophysiology, 1972, 9, 150).

[0233] Treatment success is indicated by a decrease in score.

[0234] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0235] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnia behaviors, rates their frequency, and includes outcome assessments (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0236] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0237] 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.

[0238] Treatment success is indicated by a decrease in score.

[0239] A common questionnaire for assessing 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).

[0240] Treatment response can be assessed by a reduction in score.

[0241] Fatigue is commonly assessed, for example, by the FACES (Fatigue, Lack of Energy, Awareness, Energy, Sleepiness) scale.

[0242] The FACES (Fatigue, Lack of Energy, Awareness, Energy, Sleepiness) scale is a 50-item checklist for distinguishing between tiredness, sleepiness, and fatigue. Respondents indicate the extent to which they experienced each sensation 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).

[0243] Effective treatment reduces scores on tiredness and / or fatigue and / or increases scores on the energy subscale.

[0244] Treatment response can be assessed by the above-mentioned quantitative measures, such as polysomnography or actigraphy, and / or by using the above-mentioned questionnaires. Depending on the respective sleep scale, a significant decrease or increase, respectively, in the total score, or a significant decrease, respectively, in the incidence, frequency, and impact on daily functioning, indicates treatment-induced improvement of the sleep disorder.

[0245] Common tests to 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 Disorders Assessment of DSM-5 (PID-5) - Adult.

[0246] Resting-state fMRI has been widely applied in patients with sleep disorders to improve understanding of the pathophysiology and potential compensatory mechanisms at work.

[0247] Alterations in the resting network can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders and sleep-related movement disorders.

[0248] In patients with insomnia, dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is thought to be involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain essential regions that integrate emotional and physical states, and that dysfunctional connectivity with other brain regions may underlie patients' vigilance, subjective distress, and poor sleep continuity.

[0249] For example, sleep deprivation in healthy subjects leads to changes in functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these changes in brain functional connectivity somewhat resemble vulnerability patterns in patients with Alzheimer's disease.

[0250] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, the specific DMN hubs, the precuneus and medial prefrontal cortex, show significant alterations, and functional connectivity in the DMN correlates with self-reported sleepiness severity.

[0251] Studies investigating differences between night-shift and day-shift nurses have revealed that circadian rhythm disorders contribute to altered resting-state function in the cerebellum, which is involved in sleep regulation and cognitive functions such as responsiveness and attention. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders can lead to altered brain functional connectivity. Altered resting-state brain functional connectivity has been reported in various diseases associated with circadian rhythm disorders.

[0252] Although it is technically difficult to perform functional neuroimaging during a parasomnia event, precuneus differences have been observed in arousal disorders representing parasomnias during non-REM sleep.

[0253] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information and monitoring movement. The precuneus is a subregion of the DMN. Therefore, the default mode network is affected in patients with parasomnia.

[0254] Resting-state fMRI studies in patients suffering from sleep-related breathing disorders such as obstructive sleep apnea (OSA) have demonstrated that chronic exposure to oxidative stress, intermittent hypoxia, hypocapnia and hypercapnia, and sleep fragmentation, some of the major causes of OSA brain damage, can lead to significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0255] Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in motor control pathways in the prefrontal cortex, a subregion of the default mode network, and activity in the cerebellum and thalamus can be observed, along with additional activation in the red nucleus and brainstem.

[0256] 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 result in improvement of the sleep disorder and, if the treated patient suffers from social / emotional withdrawal or isolation, will also result in improvement of social / emotional withdrawal or isolation.

[0257] Clinical data from studies of patients suffering from TRD or postpartum depression (PPD) support that sleep disorders can be successfully treated.

[0258] This study, which involved the administration of 5-MeO-DMT, specifically assessed the MADRS "decreased sleep" item (reflecting insomnia).

[0259] The MADRS "Decreased Sleep" item reflects the experience of decreased sleep duration or depth compared to the subject's own 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.

[0260] In the study group receiving the individualized dosing plan, the aggregated MADRS "Decreased Sleep" item score across all eight patients had a baseline of 25. By day 1 of treatment (the earliest time point to assess the treatment's effect on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 of treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0261] In the 12 mg group, the combined MADRS "Decreased Sleep" item score across all four patients 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.

[0262] Thus, the score for the scale item "Decreased Sleep," which is particularly relevant to sleep disorders, is 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.

[0263] 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 results in a reduction or elimination of the social / emotional withdrawal or isolation, as well as an improvement in the sleep disorder, particularly insomnia.

[0264] The reduction or elimination of social / emotional withdrawal or estrangement in patients suffering from sleep disorders, particularly insomnia, 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.

[0265] 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.

[0266] 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 scores on at least the Snaith-Hamilton Psychotherapy and Psychotherapy Pleasure Scale (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0267] 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 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to 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 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0268] Alternatively, or additionally, the reduction or elimination of social / emotional withdrawal or estrangement, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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 at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0269] 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 score on 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, particularly anhedonia, in patients suffering from a sleep disorder, particularly insomnia, as reflected by at least an improvement in the score on 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.

[0270] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly anhedonia, in a patient suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has subsided, up to the time of assessment.

[0271] In patients suffering from a sleep disorder, particularly insomnia, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. In patients suffering from a sleep disorder, particularly insomnia, the reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0272] 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 an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0273] In patients suffering from a sleep disorder, particularly insomnia, a reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. In patients suffering from a sleep disorder, particularly insomnia, the reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0274] As shown above, social / emotional withdrawal or isolation is an important aspect in patients suffering from sleep disorder, especially insomnia.Therefore, improving social / emotional withdrawal or isolation will also lead to the improvement of 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 also contribute to the overall improvement of sleep disorder, especially insomnia.

[0275] 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, the CGI-S decreases by at least two levels and / or to a score of 0. Particularly preferred is a decrease in the CGI-S by at least three levels and / or to a score of 0.

[0276] Improvement in idiopathic sleep disorders, as reflected by a decrease in CGI-S scores, in patients who also suffer from associated social / emotional withdrawal or detachment is observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0277] Improvement in idiopathic sleep disorder in patients also suffering from associated social / emotional withdrawal or isolation, as reflected by a decrease in CGI-S score in patients also suffering from associated social / emotional withdrawal or isolation, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in idiopathic sleep disorder in patients also suffering 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.

[0278] In one embodiment, improvement in idiopathic sleep disorder, as reflected by a decrease in CGI-S score, in patients who also suffer from associated social / emotional withdrawal or isolation 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.

[0279] In the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation, improvement in sleep disorders 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.

[0280] In the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation, the improvement in sleep disturbance, as reflected by a reduction in the CGI-I score or PGI-I score by at least a score of "much improved," 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.

[0281] Improvement in the case of idiopathic sleep disorders in patients who also suffer from associated social / emotional withdrawal or isolation may also be assessed by any other measure that reflects changes in sleep quality or quantity as indicated above, such as the Pittsburgh Sleep Quality Index (PSQI).

[0282] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a reduction in score, preferably (ii) to 5 or less.

[0283] Improvement in idiopathic sleep disorder, as reflected by a decrease in PSQI total score, particularly to 5 or less, in patients who also suffer from associated social / emotional withdrawal or detachment, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period extends from the time the acute hallucinatory experience after the last administration has abated to the time of assessment. Such improvement in idiopathic sleep disorder, as reflected by a decrease in PSQI total score, in patients who also suffer from associated social / emotional withdrawal or detachment, 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, wherein the recall period extends from the time the acute hallucinatory experience after the last administration has abated to the time of assessment.

[0284] Improvement in idiopathic sleep disturbance, as reflected by a decrease in PSQI total score, in patients who also suffer from associated social / emotional withdrawal or detachment is observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 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 experience following the last administration has abated to the time of assessment.

[0285] Social / emotional withdrawal or isolation and sleep disorders, especially insomnia, are closely associated with psychiatric and nervous system disorders. Both social / emotional withdrawal or isolation and sleep disorders, especially insomnia, are associated with disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, 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, such as chronic pain and It occurs in mental or nervous system disorders such as fibromyalgia; mental and behavioral disorders due to psychoactive substance use, e.g., substance use disorders (SUDs); psychotic disorders, e.g., schizophrenia; dementia, e.g., 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, e.g., schizotypal personality disorder and borderline personality disorder (BPD).

[0286] Both social / emotional withdrawal and sleep disorders, particularly insomnia, also occur in medical health conditions that lead to associated psychiatric or neurological disorders, such as traumatic brain injury (TBI).

[0287] Treatment according to the invention will result in improvement of both social / emotional withdrawal or isolation and sleep disorders, particularly insomnia, as well as improvement of associated psychiatric or neurological disorders (examples of which are listed above).

[0288] Treatment of social / emotional withdrawal or isolation and mental and neurological disorders In 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 results in an improvement in the condition associated with the social / emotional withdrawal or isolation.

[0289] Although social / emotional withdrawal or detachment may be considered a condition worthy of treatment independent of any other conditions, disorders, or symptoms from which an individual may be afflicted, 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 may psychiatric disorders have social / emotional withdrawal or detachment in the patient's emotional state, but social / emotional withdrawal or detachment may also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0290] In many cases, the resting-state networks involved in social / emotional withdrawal or detachment are also involved in the pathologies listed above.

[0291] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption leads to a reset of pathological, inappropriately connected brain connections as the networks reconnect. New, healthy functional connectivity is established, resulting in sustained effects.

[0292] A disorder characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0293] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0294] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present during the same two-week period, representing a change from previous functioning, and at least one of these symptoms being either (1) depressed mood or (2) loss of interest or pleasure.

[0295] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0296] Patients suffering from disorders characterized by depressive episodes also often suffer from social / emotional withdrawal or detachment.

[0297] Social / emotional withdrawal or detachment is included as a diagnostic criterion for disorders characterized by depressive episodes. It can be assessed as part of the MADRS or BPRS assessment.

[0298] 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.

[0299] The items are outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, inability to feel emotions, pessimistic thoughts, and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60.

[0300] The MADRS "Inability to Feel Emotions" item reflects the subjective experience of a diminished interest in one's surroundings or in activities that normally give one pleasure. There is a diminished ability to respond with appropriate emotions to surrounding situations and people. Normal interest in surroundings and other people is rated as 0; diminished ability to enjoy things that normally interest one is rated as 1, 2, or 3; loss of interest in surroundings and loss of emotion toward friends and acquaintances is rated as 3, 4, or 5; and experience of emotional numbness, inability to feel anger, deep sadness, or joy, and complete or distressing inability to care for close relatives and friends is rated as 6.

[0301] The "emotional withdrawal" item on the Brief Psychiatric Rating Scale (BPRS) reflects an inability to relate to the interviewer and the interviewer's situation. The interviewer assesses only the extent to which the patient gives the impression of being unable to make emotional contact with others in the interview situation.

[0302] The BPRS "blunted affect" item represents a decreased emotional tone, a clear lack of normal affect or engagement.

[0303] Social / emotional withdrawal or detachment or aspects thereof (such as anhedonia) in patients suffering from a disorder characterized by depressive episodes can be assessed, for example, using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0304] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity are observed within and / or between several brain regions implicated in processing, regulation, and emotional memory; cognitive processes related to rumination; and reduced concentration and physiological arousal.

[0305] 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 results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as an improvement in the disorder characterized by depressive episodes.

[0306] The reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from a disorder characterized by a depressive episode 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.

[0307] The reduction or elimination of social / emotional withdrawal or detachment 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 detachment 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.

[0308] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the score on at least 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0309] The reduction or elimination of social / emotional withdrawal or detachment, particularly the inability to have emotions, as reflected by an improvement in the score on the MADRS "Inability to Have Emotions" item in patients suffering from a disorder characterized by a depressive episode 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 MADRS "Inability to Have Emotions" item in patients 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.

[0310] 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 an improvement in the score on at least the BPRS "Emotional Withdrawal" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0311] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item in patients suffering from a disorder characterized by a depressive episode 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 "Emotional Withdrawal" item in patients 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.

[0312] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0313] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients suffering from a disorder characterized by depressive episodes occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by an improvement in the score on the BPRS "blunted affect" item. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the score on the BPRS "blunted affect" item 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.

[0314] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in scores on the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0315] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by a depressive episode, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, in patients 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0316] 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 scores on at least the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0317] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from a disorder characterized by a depressive episode, as reflected by at least an improvement in score on 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, as reflected by at least an improvement in score on the DARS, in patients 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.

[0318] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0319] In patients suffering from a disorder characterized by depressive episodes, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet in patients suffering from a disorder characterized by depressive episodes 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0320] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0321] In patients suffering from a disorder characterized by depressive episodes, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet in patients suffering from a disorder characterized by depressive episodes 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0322] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0323] In patients suffering from a disorder characterized by depressive episodes, a reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy in patients suffering from a disorder characterized by depressive episodes 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0324] 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 an improvement in the mean score on at least the Personality Disorders for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experiences following the last administration have subsided, up to the time of assessment.

[0325] In patients suffering from a disorder characterized by depressive episodes, reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. In patients suffering from a disorder characterized by depressive episodes, the reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Detachment domain, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0326] As shown above, social / emotional withdrawal or isolation is closely associated with disorders characterized by depressive episodes. Therefore, improving social / emotional withdrawal or isolation will also lead to improvement of disorders characterized by depressive episodes. Because social / emotional withdrawal or isolation also affects other aspects of disorders characterized by depressive episodes, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also additionally contribute to the overall improvement of disorders characterized by depressive episodes.

[0327] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in the disorder characterized by depressive episodes, 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] Improvement in the disorder characterized by depressive episodes, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0329] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects how a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0330] Patients with MDD may suffer from a treatment-resistant form of the disorder.

[0331] 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.These at least two previous treatment courses are particularly administered during the current depressive episode.

[0332] As outlined in the DSM-5, anhedonia is a core symptom and primary feature of MDD.

[0333] Depressive symptoms are also associated with reduced time spent in social interactions. Social withdrawal is prevalent in patients with MDD and is associated with suicidal ideation.

[0334] Social / emotional withdrawal or detachment in patients with MDD can be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects thereof, can be further assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0335] In patients with MDD, 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 is significantly different from that observed in healthy controls.

[0336] Treating patients with MDD (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as improvement of the MDD.

[0337] Patients 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. Additionally, patients 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.

[0338] The reduction or elimination of social / emotional withdrawal or estrangement in a patient with MDD 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.

[0339] 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, and 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.

[0340] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in a patient with MDD is reflected by an improvement in the score on at least 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0341] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in a patient with MDD, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, 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 a patient with MDD, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with MDD is reflected by an improvement in the score on at least the BPRS "Emotional Withdrawal" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0343] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient with MDD, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient with MDD, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient with MDD is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with MDD, as reflected by an improvement in the score on the BPRS "blunted affect" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with MDD, as reflected by an improvement in the score on the BPRS "blunted affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0346] 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 scores on at least the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0347] 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) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0348] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or distancing, particularly anhedonia, in a patient with MDD is reflected by an improvement in at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0349] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from MDD, as reflected by an improvement in at least a score on 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, as reflected by an improvement in at least a score on the DARS, in a patient suffering from 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.

[0350] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly anhedonia, in a patient with MDD is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0351] In patients with MDD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with MDD, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0352] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with MDD is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0353] In patients with MDD, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with MDD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0354] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with MDD is reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0355] In patients with MDD, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with MDD, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0356] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with MDD is reflected by an improvement in the mean score on at least the Personality Disorders for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0357] The reduction or elimination of social / emotional withdrawal or detachment in patients with MDD, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time when the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with MDD, as reflected by an improvement in the mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, 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, wherein the recall period begins no earlier than the time when the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0358] As shown above, social / emotional withdrawal or isolation is closely related to MDD.Therefore, improving social / emotional withdrawal or isolation will also lead to improvement of MDD.Because social / emotional withdrawal or isolation also affects other aspects of MDD, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also contribute to the overall improvement of MDD.

[0359] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in MDD, 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 at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0360] Improvement in MDD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in MDD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0361] A further aspect of MDD that can be treated by administration of 5-MeO-DMT in patients who also suffer from associated social / emotional withdrawal or isolation 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 the patient.

[0362] In the aforementioned clinical study of patients suffering from TRD with the administration of 5-MeO-DMT, the MADRS "suicidal thoughts" item was assessed, among other things.

[0363] "Suicidal thoughts" refers to feelings that life is not worth living, that one would be happy to die a natural death, having suicidal thoughts, and / or making preparations to commit suicide. Suicide attempts themselves should not affect the rating of this MADRS item.

[0364] 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 / or has only occasional suicidal thoughts. A score of 4 means the patient feels better off dead, has frequent suicidal thoughts, and considers suicide a possible solution, but the patient has no specific plan or intention. A score of 6 is assigned if the patient has a clear plan and / or is actively preparing for suicide.

[0365] This MADRS scale item is particularly relevant to suicidal ideation.

[0366] In the study group receiving the individualized dosing plan, the combined MADRS "suicidal thoughts" item score across all eight patients had a baseline of 11. After two hours, the score had decreased to 3, corresponding to an 8-point or 73% improvement. One day after treatment, the score had decreased to 1, corresponding to a 10-point or 91% improvement. Seven days after treatment, the score had decreased to 3, corresponding to an 8-point or 73% improvement.

[0367] In the 12 mg group, the combined MADRS "suicidal thoughts" item score across all four patients had a baseline of 8. After 2 hours, the score had decreased to 3, corresponding to a 5-point or 63% improvement. On day 1 after treatment, the score had decreased to 5, corresponding to a 3-point or 38% improvement. On day 7 after treatment, the score had decreased to 7, corresponding to a 1-point or 13% improvement.

[0368] Thus, scores on the scale item "Suicidal Thoughts," which is particularly relevant to suicidal ideation, are significantly improved in patients, at least on the individualized dosing regimen. The inventors conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with MDD.

[0369] 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.

[0370] Reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or detachment is reflected by an improvement in the score on the suicidal thoughts item of the MADRS 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.

[0371] The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or isolation, as reflected by an improvement in at least the score on the suicidal ideation item of the MADRS, 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 an improvement in at least the score on the suicidal ideation item of the MADRS, 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.

[0372] In comparison to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT or a pharmaceutically acceptable salt thereof can be administered, preferably using the administration schemes described herein, to patients suffering from MDD associated with social / emotional withdrawal or detachment without significant risk of inducing mania or hypomania.

[0373] Preferably, patients suffering from MDD associated with social / emotional withdrawal or distancing do not experience treatment-emergent mania or hypomania.

[0374] Bipolar disorder (BD) is a mental health disorder characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). BD is a chronic, relapsing illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0375] BD is classified as bipolar I disorder if there has been at least one manic episode, with or without depressive episodes. BD is classified as bipolar II disorder if there has been at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode. If these symptoms are due to drugs or medical problems, they are not diagnosed as bipolar disorder.

[0376] Patients with BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0377] 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.These at least two previous treatment courses are particularly administered during the current depressive episode.

[0378] Distinct brain regions in patients with bipolar I and II disorder have been implicated in emotional blunting and emotional withdrawal.

[0379] In a study of 197 adolescents with bipolar disorder, anhedonia was present during severe depressive episodes in 90.9% of individuals. Symptom severity was significantly associated with the severity of the disorder.

[0380] 0.5mg kg -1A single ketamine infusion rapidly reduced anhedonia levels in patients with treatment-resistant bipolar depression. This single infusion produced effects within 40 minutes and lasted for up to 14 days. Positron emission tomography (PET) scans of a subset of these individuals revealed that the anti-anhedonia effect was due, in part, to increased glucose metabolism in the dorsal anterior cingulate cortex (an element of the DAN) and putamen (part of the basal ganglia RSN).

[0381] Social / emotional withdrawal or detachment in patients with BD can be assessed as part of the MADRS, BPRS, or BDRS assessment. Social / emotional withdrawal or detachment, or at least aspects thereof, can be further assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0382] 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 current and past few days' symptoms, the current symptoms should be reflected in the assessment. The scale contains 20 questions, with a maximum possible score of 60. Higher scores indicate greater severity.

[0383] Questions address depressed mood, sleep disturbances, appetite disturbances, decreased social interaction, decreased energy and activity, decreased motivation, impaired concentration and memory, anxiety, anhedonia, flat affect, feelings of worthlessness, feelings of powerlessness and hopelessness, suicidal thoughts, guilt, psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation.

[0384] Each of these aspects is assessed and assigned a score of 0, 1, 2, or 3.

[0385] The BDRS "Decreased Social Engagement" item reports on decreased social and interpersonal engagement or interaction. Normal social engagement is scored as 0, slightly decreased social engagement but no impairment in social or interpersonal functioning is scored as 1 (mild), clearly decreased social engagement with some functional sequelae (e.g., avoidance of some social engagement or conversation) is scored as 2 (moderate), and severe social interaction is significantly reduced or almost all forms of social contact are avoided (e.g., patient refuses to answer the phone or meet with friends or family).

[0386] The BPRS "anhedonia" item concerns a subjective decrease in the ability to experience pleasure in everyday activities. Anhedonia is scored as 0 if there is no subjective decrease in the ability to experience pleasure in everyday activities, 1 (mild) if there is a slight decrease in pleasure from usual pleasurable activities, 2 (moderate) if there is a marked decrease in pleasure from usual pleasurable activities with some maintained pleasure from isolated activities, and 3 (severe) if there is a complete inability to experience pleasure.

[0387] The BDRS "flattened affect" item is the subjective sensation of a decrease in the intensity or range of emotions or feelings. Flattened affect is scored as 0 if there is no subjective sensation of a decrease in the intensity or range of emotions or feelings; 1 (mild) if there is a slight decrease in the range of emotions or a transient decrease in the range or intensity of emotions; 2 (moderate) if there is a significant decrease in the range or intensity of emotions, but some emotions are preserved (e.g., inability to cry); and 3 (severe) if there is a significant and total decrease in the range of emotions or an inability to experience normal emotions.

[0388] Patients with bipolar disorder exhibit characteristic abnormalities in the 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.

[0389] Treatment of patients with BD (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as improvement of the BD.

[0390] Typically, patients with BD, whether diagnosed with bipolar II disorder or bipolar I disorder, suffer from a current major depressive episode.

[0391] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient's total score can be 19 or higher, e.g., 24 or higher, and especially 37 or higher.

[0392] 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.

[0393] The reduction or elimination of social / emotional withdrawal or estrangement in a patient suffering from bipolar disorder 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.

[0394] 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.

[0395] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in patients with BD is reflected by an improvement in the score on at least 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0396] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in patients with BD, as reflected by an improvement in the MADRS "Inability to Feel" item 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 emotional inability, in patients with BD, as reflected by an improvement in the MADRS "Inability to Feel" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0397] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient with BD is reflected by an improvement in the score on at least the BPRS "Emotional Withdrawal" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0398] 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 "Emotional Withdrawal" item 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 "Emotional Withdrawal" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0399] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient with BD is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0400] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with BD, as reflected by an improvement in the score on the BPRS "blunted affect" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with BD, as reflected by an improvement in the score on the BPRS "blunted affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0401] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly decreased social engagement, in a patient with BD is reflected by an improvement in the score for at least the "Decreased Social Engagement" item on the BDRS 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 at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0402] The reduction or elimination of social / emotional withdrawal or isolation, particularly reduced social engagement, in a patient with BD, as reflected by an improvement in the score on the BDRS "Decreased Social Engagement" item 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 a patient with BD, as reflected by an improvement in the score on the BDRS "Decreased Social Engagement" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0403] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from BD is reflected by an improvement in the score on at least the BDRS "Anhedonia" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0404] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by an improvement in the score on the BDRS "Anhedonia" item, 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 patients with BD, as reflected by an improvement in the score on the BDRS "Anhedonia" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0405] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly flat affect, in a patient suffering from BD is reflected by an improvement in the score on at least the BDRS "Flat Affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0406] 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 "Flat Affect" item, 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 "Flat Affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0407] Alternatively, or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from BD is reflected by an improvement in scores on the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0408] 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) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0409] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD is reflected by an improvement in scores on at least the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] 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 score on 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, as reflected by at least an improvement in the score on the DARS, 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.

[0411] 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 mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0412] In patients with BD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with a recall period beginning no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with BD, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0413] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with BD is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0414] In patients with BD, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with BD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0415] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with BD is reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0416] In patients with BD, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with BD, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0417] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with BD is reflected by an improvement in the mean score on at least the Personality Disorders for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0418] The reduction or elimination of social / emotional withdrawal or detachment in patients with BD, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time when the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with BD, as reflected by an improvement in the mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, 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, wherein the recall period begins no earlier than the time when the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0419] As shown above, social / emotional withdrawal or isolation is closely associated with BD. Therefore, improvement of social / emotional withdrawal or isolation will also lead to improvement of BD. Because social / emotional withdrawal or isolation also affects other aspects of BD, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also additionally contribute to the overall improvement of BD.

[0420] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in BD, 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.

[0421] Improvement in BD, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in bipolar disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0422] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, can be administered, preferably using the administration schemes described herein, to patients suffering from bipolar disorders associated with social / emotional withdrawal or detachment (such as bipolar I disorder and bipolar II disorder) without significant risk of inducing mania or hypomania.

[0423] Preferably, patients suffering from bipolar disorders associated with social / emotional withdrawal or detachment (such as bipolar I disorder and bipolar II disorder) do not experience treatment-emergent mania or hypomania.

[0424] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks of delivery. While over 50% of women may experience short-term low mood or tearfulness after giving birth, a subset of women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0425] Patients with PPD may suffer from a treatment-resistant form of the disorder.

[0426] An analysis of data from 663 women with perinatal depression found that anhedonia and anxiety were prominent symptoms eight weeks postpartum.

[0427] Social isolation is one of five identified dimensions that correlate with and predict maternal depressive symptoms.

[0428] PPD is also known as perinatal-onset major depressive disorder. According to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), PPD is diagnosed when symptoms of major depressive disorder (MDD) begin during pregnancy or within four weeks after delivery. Therefore, PPD patients also suffer from social / emotional withdrawal or detachment, especially anhedonia.

[0429] Social / emotional withdrawal or detachment in patients suffering from PPD can be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects thereof, can be further assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0430] Patients with PPD exhibit significant alterations in neural activity within brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with dysfunctional connectivity within and / or between resting-state networks, such as the default mode network and the frontoparietal network.

[0431] Treating patients with PPD (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as improvement of the PPD.

[0432] Patients 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. Additionally, patients 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.

[0433] 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.

[0434] Additionally, patients undergoing treatment according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0435] Furthermore, 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.

[0436] The reduction or elimination of social / emotional withdrawal or estrangement in patients with PPD 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.

[0437] 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.

[0438] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in patients with PPD is reflected by an improvement in the score on at least 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0439] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in a patient with PPD, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, 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 a patient with PPD, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0440] 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 at least the BPRS "Emotional Withdrawal" 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), 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 emotional withdrawal, in a patient with PPD, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient with PPD, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0442] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient with PPD is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0443] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with PPD, as reflected by an improvement in the score on the BPRS "blunted affect" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients with PPD, as reflected by an improvement in the score on the BPRS "blunted affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] 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 scores on at least the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0445] 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 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 no earlier than the time the acute hallucinatory experience following the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, in patients 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, with the recall period beginning no earlier than the time the acute hallucinatory experience following the last administration has subsided, up to the time of assessment.

[0446] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with PPD is reflected by an improvement in scores on at least the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0447] 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 score on 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, as reflected by at least an improvement in the score on the DARS, 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.

[0448] Alternatively, or additionally, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with PPD is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0449] In patients with PPD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with PPD, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0450] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with PPD is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0451] In patients with PPD, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with PPD, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0452] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly emotional withdrawal, in a patient with PPD is reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0453] In patients with PPD, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients with PPD, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0454] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient with PPD is reflected by an improvement in the mean score on at least the Personality Disorders for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0455] The reduction or elimination of social / emotional withdrawal or detachment in patients with PPD, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time when the acute hallucinatory experiences following the last administration have subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment in patients with PPD, as reflected by an improvement in the mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5) - Adult Detachment, 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 no earlier than the time when the acute hallucinatory experiences following the last administration have subsided, up to the time of assessment.

[0456] As shown above, social / emotional withdrawal or isolation is closely related to PPD.Therefore, improving social / emotional withdrawal or isolation will also lead to improvement of PPD.Because social / emotional withdrawal or isolation also affects other aspects of PPD, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also contribute to the overall improvement of PPD.

[0457] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in PPD, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last dose 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 at 28 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0458] Improvement in PPD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PPD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0459] Social / emotional withdrawal or estrangement further impairs maternal functioning.

[0460] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index was designed to measure functioning during the first year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6, resulting in a maximum total score of 120. A higher score indicates better maternal functioning.

[0461] The BIMF identifies the following key functional domains for mothers during the postnatal period: self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0462] A BIMF score of 95 or less is considered herein to represent a slight decline in maternal functioning, a score of 80 or less is considered herein to represent a decline in maternal functioning, and a score of 65 or less is considered herein to represent a severe decline in maternal functioning.

[0463] The inventors have determined that elevations in the MADRS "unable to have emotions" item and / or the BPRS "emotional withdrawal" and "blunted affect" item scores have a negative impact on maternal functioning (the mother's ability to interact with her infant(s) and her self-care).

[0464] Increased scores on the MADRS Unable to Feel and / or the BPRS Emotional Withdrawal and / or Affectively Flattened items impair psychological well-being, social support, and control. Conversely, improvements on the MADRS Unable to Feel and / or the BPRS Emotional Withdrawal and Affectively Flattened items result in improvements in maternal functioning, particularly the psychological well-being, social support, and / or control functional domains of the BIMF.

[0465] The inventors conclude that treating PPD patients with 5-MeO-DMT can achieve improvement in social / emotional withdrawal or detachment, particularly reduction or elimination of emotionlessness, emotional withdrawal, and / or blunted affect.

[0466] The inventors further conclude that treating PPD patients by reducing or eliminating the inability to have emotions, emotional withdrawal, and / or blunted affect not only results in a decrease in the MADRS or BPRS total score, but also in improved maternal functioning as reflected by an increase in the BIMF score.

[0467] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0468] Improvement in maternal function in patients with PPD is reflected by an improvement in at least 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.

[0469] In patients with PPD, improvement in maternal function, as reflected by at least an improvement in the BIMF total score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by at least an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0470] 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 associated with social / emotional withdrawal or detachment without significant risk of inducing mania or hypomania, preferably using the administration schemes described herein.

[0471] Preferably, patients suffering from PPD associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0472] Seasonal affective disorder is a seasonal mood disorder whose symptoms often begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0473] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0474] 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.

[0475] Social / emotional withdrawal or detachment in patients with seasonal affective disorder can be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects thereof, can be further assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorder Assessment for DSM-5 (PID-5) - Adult.

[0476] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0477] In patients with seasonal affective disorder, altered functional connectivity has been observed within and / or among several brain regions implicated in processing, regulation, and emotional memory; cognitive processes related to rumination; and reduced focus and physiological arousal. Dysfunctional connectivity has been observed within and / or among the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0478] Treatment of patients with seasonal affective disorder (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as improvement of the seasonal affective disorder.

[0479] The reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from seasonal affective disorder 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.

[0480] 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.

[0481] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on at least 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0482] The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional inability, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, 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 a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the MADRS "Inability to Feel" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0483] 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 an improvement in the score on at least the BPRS "Emotional Withdrawal" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] 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 "Emotional Withdrawal" item, 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 "Emotional Withdrawal" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0486] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the BPRS "blunted affect" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the score on the BPRS "blunted affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] 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 scores on the Snaith-Hamilton Psychological Aptitude Test (SHAPS) 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0488] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from seasonal affective disorder, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score in patients 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0489] Alternatively, or additionally, 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 at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0490] 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 score on 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, as reflected by at least an improvement in the score on the DARS, 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.

[0491] Alternatively, or additionally, 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 mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0492] In patients suffering from seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0493] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from seasonal affective disorder is reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0494] In patients with seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0495] 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 an improvement in the mean score of at least the trait facet of the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0496] In patients with seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0497] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from seasonal affective disorder is reflected by an improvement in the mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0498] In patients with seasonal affective disorder, reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. In patients suffering from seasonal affective disorder, the reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score on at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Detachment domain, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0499] As shown above, social / emotional withdrawal or isolation is closely related to seasonal affective disorder.Therefore, improving social / emotional withdrawal or isolation will also lead to 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 in social / emotional withdrawal or isolation will also contribute to the overall improvement of seasonal affective disorder.

[0500] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in seasonal affective disorder, 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 at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0501] Improvement in seasonal affective disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0502] In comparison to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT or a pharmaceutically acceptable salt thereof can be administered, preferably using the administration schemes described herein, to patients suffering from seasonal affective disorder, which is associated with social / emotional withdrawal or detachment, without significant risk of inducing mania or hypomania.

[0503] Preferably, patients suffering from seasonal affective disorder associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0504] Persistent depressive disorder Persistent depressive disorder (also called dysthymia) is a chronic form of depression. A diagnosis of persistent depressive disorder is made when depression is present most days of the day for at least two years, with symptom-free periods lasting less than two months.

[0505] During a depressive episode, two or more of the following must be present: 1. Hopelessness; 2. Low energy or fatigue; 3. Low self-esteem; 4. Decreased sleep (insomnia) or increased sleep (hypersomnia); 5. Poor appetite or overeating; 6. Difficulty making decisions or poor concentration.

[0506] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0507] According to the DSM-V, persistent depressive disorder may be characterized by the criteria of major depressive disorder, including anhedonia, which may be present continuously for two years. Social withdrawal is also a common symptom in patients with persistent depressive disorder.

[0508] Social / emotional withdrawal or detachment in patients with persistent depressive disorder can be assessed as part of the MADRS or BPRS assessment. Social / emotional withdrawal or detachment, or at least aspects thereof, can be further assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0509] In patients with persistent depressive disorder, altered functional connectivity has been observed within and / or among several brain regions implicated in processing, regulation, emotional memory; cognitive processes related to rumination; and reduced focus and physiological arousal. Dysfunctional connectivity has been observed within and / or among the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0510] In patients with persistent depressive disorder, dysfunctional connectivity and regulation is observed among multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0511] Treatment of patients with persistent depressive disorder (including treatment-resistant disorders) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as an improvement in the persistent depressive disorder.

[0512] The reduction or elimination of social / emotional withdrawal or estrangement in patients with persistent depressive disorder 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.

[0513] The reduction or elimination of social / emotional withdrawal or isolation in a patient suffering from a persistent depressive 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 a persistent depressive 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.

[0514] Reduction or elimination of social / emotional withdrawal or detachment, particularly inability to have emotions, in patients with persistent depressive disorder is reflected by an improvement in the score on at least 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), 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 inability, as reflected by an improvement in the score on the MADRS "Inability to Feel" item in patients suffering from persistent depressive disorder 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, as reflected by an improvement in the score on the MADRS "Inability to Feel" item in patients suffering from persistent depressive 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.

[0516] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from a persistent depressive disorder is reflected by an improvement in the score on at least the BPRS "Emotional Withdrawal" 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), 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 detachment, particularly emotional withdrawal, in patients suffering from persistent depressive disorder, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in patients suffering from persistent depressive disorder, as reflected by an improvement in the score on the BPRS "Emotional Withdrawal" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in a patient suffering from a persistent depressive disorder is reflected by an improvement in the score on at least the BPRS "blunted affect" 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0519] The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients suffering from persistent depressive disorder, as reflected by an improvement in the score on the BPRS "blunted affect" item, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of social / emotional withdrawal or detachment, particularly blunted affect, in patients suffering from persistent depressive disorder, as reflected by an improvement in the score on the BPRS "blunted affect" item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0520] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from a persistent depressive disorder is reflected by an improvement in scores on the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0521] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depressive disorder, as reflected by at least an improvement in the Snaith-Hamilton Symptom Pleasure Scale (SHAPS) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time when the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, in patients suffering from persistent depressive 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, wherein the recall period begins no earlier than the time when the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0522] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depressive disorder is reflected by an improvement in scores on at least the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0523] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depressive disorder, as reflected by at least an improvement in score on 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, as reflected by at least an improvement in score on the DARS, in patients suffering from persistent depressive 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.

[0524] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients suffering from persistent depressive disorder is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait 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 no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0525] In patients with persistent depressive disorder, a reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet in patients suffering from persistent depressive disorder 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0526] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from a persistent depressive disorder is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0527] In patients with persistent depressive disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients suffering from persistent depressive disorder, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0528] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, in a patient suffering from a persistent depressive disorder is reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders for DSM-5 (PID-5)-Adult Avoidance of Intimacy 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0529] In patients with persistent depressive disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly emotional withdrawal, as reflected by an improvement in the mean score of at least the trait facet of the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Avoidance of Intimacy in patients suffering from persistent depressive disorder 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0530] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment in a patient suffering from a persistent depressive disorder is reflected by an improvement in the mean score on at least the Personality Disorders for DSM-5 (PID-5)-Adult Detachment domain 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0531] In patients with persistent depressive disorder, reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score on at least the trait domain of the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. In patients suffering from persistent depressive disorder, the reduction or elimination of social / emotional withdrawal or detachment, as reflected by an improvement in the mean score on at least the Personality Disorder Assessment of DSM-5 (PID-5)-Adult Detachment domain, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0532] As shown above, social / emotional withdrawal or isolation is closely associated with persistent depressive disorder. Therefore, improvement of social / emotional withdrawal or isolation will also lead to improvement of persistent depressive disorder. Because social / emotional withdrawal or isolation also affects other aspects of persistent depressive disorder, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also additionally contribute to the overall improvement of persistent depressive disorder.

[0533] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in persistent depressive disorder, 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.

[0534] Improvement in persistent depressive disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in persistent depressive disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0535] In comparison to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT or a pharmaceutically acceptable salt thereof can be administered, preferably using the administration schemes described herein, to patients suffering from persistent depressive disorders associated with social / emotional withdrawal or detachment without significant risk of inducing mania or hypomania.

[0536] Preferably, patients suffering from persistent depressive disorder associated with social / emotional withdrawal or detachment do not experience treatment-emergent mania or hypomania.

[0537] Anxiety disorders Anxiety disorders are a type of mental health disorder. Symptoms include tension, panic, and fear, as well as sweating and increased heart rate. Anxiety is associated with fear and manifests as a future-oriented mood state consisting of complex cognitive, emotional, physiological, and behavioral response systems related to preparation for anticipated events or situations that are perceived as threatening.

[0538] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0539] Social / emotional withdrawal or detachment or at least aspects thereof can be assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0540] Anxiety disorders are associated with altered functional connectivity of resting-state networks. Anxiety disorders exhibit abnormalities in the default mode network (DMN), which influences the sense of self; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. Resting-state balance within and / or between each of these networks (e.g., SMN and SN relative to DMN) may be abnormal in various anxiety disorders.

[0541] Treatment of patients suffering from an anxiety disorder (including treatment-resistant disorders) and associated social / emotional withdrawal or isolation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or isolation, as well as improvement of the anxiety disorder.

[0542] The reduction or elimination of social / emotional withdrawal or estrangement in a patient suffering from an anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 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.

[0543] 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.

[0544] Reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from an anxiety disorder is reflected by an improvement in scores on at least the Snaith-Hamilton Scale for Psychological Pleasure (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0545] 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 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score in patients 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0546] 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 an improvement in at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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, at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] 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 score on 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, as reflected by at least an improvement in score on the DARS, 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.

[0548] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from an anxiety disorder is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0549] In patients suffering from an anxiety disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to 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 an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0550] 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 an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0551] In patients suffering from an anxiety disorder, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to 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 an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0552] As shown above, social / emotional withdrawal or isolation occurs in patients with anxiety disorders.Therefore, improving social / emotional withdrawal or isolation will also lead to improvement of anxiety disorders.Since social / emotional withdrawal or isolation also affects other aspects of anxiety disorders, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also contribute to the overall improvement of anxiety disorders.

[0553] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in anxiety disorders, 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.

[0554] Improvement in anxiety disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in anxiety disorder, as reflected by a decrease in CGI-S score in patients who also suffer from associated social / emotional withdrawal or detachment, 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] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry about a wide range of situations and problems. Patients with GAD may anticipate disaster and worry excessively about money, health, family, work, or other problems.

[0556] 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 persist for months to years.

[0557] GAD interferes with social, occupational, or other important areas of functioning.

[0558] Patients with GAD may suffer from a treatment-resistant form of the disorder.

[0559] In a study of 224 individuals primarily diagnosed with GAD, anhedonia was found to be a crucial component of the association between quality of life (QoL), sleep problems, and negative cognitions.

[0560] A large longitudinal study of older adults found that social isolation was associated with higher anxiety and depressive symptoms.

[0561] Social / emotional withdrawal or detachment or at least aspects thereof can be assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0562] Patients with GAD exhibit altered functional connectivity, particularly within the default mode network.

[0563] Treating patients with GAD (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as an improvement in GAD.

[0564] The reduction or elimination of social / emotional withdrawal or estrangement in patients with GAD 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.

[0565] 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.

[0566] Reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with GAD is reflected by an improvement in scores on at least the Snaith-Hamilton Psychological Acuity Scale (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0567] 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) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0568] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with GAD is reflected by an improvement in at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0569] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by at least an improvement in score on 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, as reflected by at least an improvement in score on the DARS, 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.

[0570] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient with GAD is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0571] In patients with GAD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with GAD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0572] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient with GAD is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0573] In patients with GAD, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with GAD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0574] As shown above, social / emotional withdrawal or isolation occurs in patients with GAD. Therefore, improvement of social / emotional withdrawal or isolation will also lead to improvement of GAD. Because social / emotional withdrawal or isolation also affects other aspects of GAD, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also additionally contribute to the overall improvement of GAD.

[0575] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in GAD, 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.

[0576] Improvement in GAD, as reflected by a reduction in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in GAD, as reflected by a reduction in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0577] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types 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 and can cause impairment in functioning at school, work, or in relationships.

[0578] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations.

[0579] Patients with SAD may suffer from a treatment-resistant form of the disorder.

[0580] Social withdrawal is a core feature of SAD, characterized by fear and avoidance of social interactions. Social avoidance is also seen in SAD, and patients with comorbid major depression show higher social avoidance scores than those with SAD alone.

[0581] Avoidance of social situations and increased time spent alone may reflect the behavioral consequences of anhedonia, but reduced time in social situations also increases anhedonia, establishing a vicious cycle of withdrawal and deterioration, increasing social isolation.

[0582] Social / emotional withdrawal or detachment or at least aspects thereof can be assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedonia Rating Scale (DARS) or the Personality Disorders Assessment of DSM-5 (PID-5) - Adult.

[0583] In patients with SAD, altered functional connectivity is observed in the default mode network and salience network.

[0584] Treating patients with SAD (including treatment-resistant forms of the disorder) and suffering from associated social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in a reduction or elimination of the social / emotional withdrawal or detachment, as well as improvement of the SAD.

[0585] The reduction or elimination of social / emotional withdrawal or estrangement in patients with SAD 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.

[0586] The reduction or elimination of social / emotional withdrawal or isolation in a patient with SAD 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 SAD 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.

[0587] Reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from SAD is reflected by an improvement in scores on at least the Snaith-Hamilton Psychological Acuity Pleasure Scale (SHAPS) 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0588] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with SAD, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, as reflected by at least an improvement in the SHAPS score in patients with SAD, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided, up to the time of assessment.

[0589] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from SAD is reflected by an improvement in at least the score on the Dimensional Anhedonia Rating Scale (DARS) 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with SAD, as reflected by at least an improvement in score on 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, as reflected by at least an improvement in score on the DARS, in patients with SAD, 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.

[0591] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in a patient suffering from SAD is reflected by an improvement in the mean score on at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet 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), 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 no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0592] In patients with SAD, reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly anhedonia, in patients with SAD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Anhedonia Trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0593] Alternatively, or additionally, reduction or elimination of social / emotional withdrawal or estrangement, particularly social withdrawal, in a patient suffering from SAD is reflected by an improvement in the mean score of at least the Personality Disorders for DSM-5 (PID-5)-Adult Withdrawal trait facet 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), 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 no earlier than the time the acute hallucinatory experiences after the last administration have subsided, up to the time of assessment.

[0594] In patients with SAD, reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, as reflected by an improvement in the mean score of at least the Personality Disorders Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment. The reduction or elimination of social / emotional withdrawal or detachment, particularly social withdrawal, in patients with SAD, as reflected by an improvement in the mean score of at least the Personality Disorder Assessment for DSM-5 (PID-5)-Adult Withdrawal trait facet, 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, wherein the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has abated, up to the time of assessment.

[0595] As shown above, social / emotional withdrawal or isolation occurs in patients with SAD. Therefore, improving social / emotional withdrawal or isolation will also lead to improvement of SAD. Because social / emotional withdrawal or isolation also affects other aspects of SAD, the inventors conclude that the observed improvement in social / emotional withdrawal or isolation will also contribute to the overall improvement of SAD.

[0596] In patients who also suffer from associated social / emotional withdrawal or detachment, improvement in SAD, 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), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0597] Improvement in SAD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD, as reflected by a decrease in CGI-S scores in patients who also suffer from associated social / emotional withdrawal or detachment, 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.

[0598] Obsessive-compulsive disorder and related disorders Obsessive-compulsive disorder (OCD) is a mental illness that causes recurring unwanted thoughts or feelings (obsessions) or repeated urges to perform certain actions (compulsions). Patients may suffer from both obsessions and compulsions.

[0599] Patients with OCD may suffer from a treatment-resistant form of the disorder.

[0600] Anhedonia is suggested to be a mechanism mediating the comorbid relationship between OCD and MDD symptoms in adolescents.

[0601] A relationship between OCD symptoms and anhedonia independent of depression has also been found.

[0602] Social / emotional withdrawal or detachment or at least aspects thereof can be assessed, for example, by using the Snaith-Hamilton Pleasure Scale (SHAPS) or the Dimensional Anhedon...

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, wherein the 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously.

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 loss of pleasure, emotional withdrawal, flattening of emotions, and / or a decrease in social interaction.

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

5. The pharmaceutical composition according to claim 2, wherein the reduction or elimination of the 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 (e.g., about 24 hours after), at least seven days after, at least fourteen days after, and / or at least twenty-eight days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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 the aforementioned mental disorder or the aforementioned nervous system disorder is suffering from a treatment-resistant type of the aforementioned disorder.

8. The pharmaceutical composition according to claim 7, wherein the patient is currently suffering from a major depressive episode.

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

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 10, wherein the patient suffering from the aforementioned MDD is suffering from a treatment-resistant type of the aforementioned disorder.

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

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

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 dosage regimen that causes the patient to experience a hallucinogenic peak experience.

15. 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.

16. 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.

17. The pharmaceutical composition according to claim 16, wherein each subsequent dose is administered in a larger amount than the previous dose.

18. The pharmaceutical composition according to claim 16, wherein the patient is administered subsequent doses unless he or she experiences a hallucinatory peak experience.

19. The pharmaceutical composition according to claim 16, 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.

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

21. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous injection.