5-methoxy-n, n-dimethyltryptamine for treatment of social / emotional recession or distraction

Abstract

5-methoxyl-N, N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient suffering from social / emotional recession or distraction wherein the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is administered via the intravenous, intramuscular or subcutaneous route.

Description

Technical Field

[0001] This invention relates to an improved method for treating social / emotional withdrawal or detachment, particularly for patients suffering from mental or neurological disorders, such as disorders characterized by depressive episodes, including major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I and bipolar II), postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); and obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and physical dysmorphic disorder. (BDD); Post-traumatic stress disorder (PTSD); Pain disorders, such as chronic pain and fibromyalgia; Mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorder (SUD); Psychotic disorders, such as schizophrenia; Dementia, such as Alzheimer's dementia (AD); Lewy body dementia (DLB); Vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); Eating disorders; Autism spectrum disorder (ASD); Attention deficit hyperactivity disorder (ADHD); and Personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0002] Social / emotional withdrawal or alienation can also occur in patients with sleep disorders (such as insomnia).

[0003] Social / emotional withdrawal or alienation can also occur in patients with medical conditions that lead to related mental or neurological disorders, including traumatic brain injury (TBI).

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

[0005] Symptoms such as anhedonia, emotional withdrawal, and emotional detachment are grouped together here as social / emotional withdrawal or alienation. Reduced social engagement is another aspect associated with social / emotional withdrawal or alienation.

[0006] Anhedonia is the inability to experience pleasure. It occurs when a patient's ability to subjectively experience pleasure in daily activities declines. Anhedonia includes consumptive (or liking) and anticipatory (or wanting) components. Consumptive pleasure refers to the immediate pleasure experienced when directly engaging in pleasurable activities, while anticipatory pleasure refers to pleasurable experiences related to future activities.

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

[0008] Emotional apathy is characterized by a subjective feeling of reduced intensity or range of sensations or emotions.

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

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

[0011] Therefore, there is a need for improved methods to treat social / emotional withdrawal or alienation, especially social / emotional withdrawal or alienation associated with mental or neurological disorders. Summary of the Invention

[0012] One object of the present invention is particularly to provide an improved therapy that is more effective than the previously described therapy (i.e., a) a larger percentage of patients experience a clinical response, b) a larger average clinical response, c) an earlier clinical response, and / or d) a more durable clinical response).

[0013] A further object of the present invention is to provide compounds for improved psychoactive therapies and administration regimens for said therapies, said therapies having better safety and / or better tolerability than previously described therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and administration regimens for said therapies, said therapies being more convenient than previously described therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and administration regimens for said therapies, said therapies being associated with higher patient adherence rates (including higher treatment initiation rates) compared to previously described therapies. A further object of the present invention is to identify specific disease aspects and subgroups of specific disease aspects that benefit from such improved psychoactive therapies.

[0014] This invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for the treatment of patients suffering from social / emotional withdrawal or alienation, particularly symptoms such as anhedonia, emotional withdrawal, emotional apathy and / or reduced social engagement.

[0015] This invention provides an improved method for treating social / emotional withdrawal or alienation, particularly in patients suffering from mental or neurological disorders such as those characterized by depressive episodes, including major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I and bipolar II), 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 physical deformities. Disorders such as: BDD; post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); Lewy body dementia (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0016] The present invention also provides an improved method for treating social / emotional withdrawal or alienation in patients suffering from sleep disorders (such as insomnia).

[0017] The present invention also provides an improved method for treating social / emotional withdrawal or alienation in patients suffering from medical conditions that lead to related mental or neurological disorders, including traumatic brain injury (TBI).

[0018] The present invention also provides dosage ranges and dosing regimens for treating social / emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, emotional apathy and / or reduced social engagement.

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

[0020] 5-MeO-DMT or a pharmaceutically acceptable salt thereof may be administered at a dose or dosing regimen that induces a peak psychedelic experience 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 may be administered. Detailed Implementation

[0021] definition

[0022] As used in the context of this invention, unless otherwise stated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. Pharmaceutically acceptable salts of 5-MeO-DMT may also be considered. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and trifluoromethanesulfonic acid. A preferred example is hydrobromide. Assuming the use of equimolar amounts, the appropriate weight of the salt to be applied can be calculated based on the weight of the free base.

[0023] As used in the context of this invention, the “patient” to be treated is a human subject diagnosed by a practicing professional in accordance with recognized medical practice as having social / emotional withdrawal or alienation, or diagnosed by a practicing professional in accordance with recognized medical practice as having a mental or neurological disorder associated with social / emotional withdrawal or alienation. In the latter case, assessing social / emotional withdrawal or alienation may or may not be part of the diagnosis.

[0024] For example, the diagnosis of mental disorders or neurological disorders can be made 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 situations below, the criteria may be modified or supplemented to better define patients or patient groups who particularly benefit from treatment according to the present invention. In any case, the diagnosis will be made by a physician or psychologist. It is not sufficient for the subject to believe that they have the stated disorder.

[0025] As used in the context of this invention, unless otherwise stated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, ailment, or disorder, and include the administration of compounds and methods according to the invention to alleviate the signs and / or symptoms of a disease or to eliminate the disease, ailment, or disorder.

[0026] "Treatment of social / emotional withdrawal or alienation" should include the management and care of patients for the purpose of combating social / emotional withdrawal or alienation, and include the administration of compounds and methods according to the invention to alleviate the signs and / or symptoms of social / emotional withdrawal or alienation or to eliminate social / emotional withdrawal or alienation.

[0027] Social / emotional withdrawal or alienation can be associated with sleep disorders (such as insomnia), mental disorders or neurological disorders or other medical conditions.

[0028] The patient may have a treatment-resistant disorder. Treatment resistance means that the patient has not achieved adequate improvement after at least two adequate courses of treatment. This is particularly true when the patient has not achieved adequate improvement after at least two adequate courses of treatment, where at least one of these courses is pharmacological therapy; for example, the patient has not achieved adequate improvement after at least two adequate courses of medication. Specifically, this involves the administration of at least two prior courses of treatment during the current episode of the disorder, for example, if the patient suffers from a disorder characterized by depressive episodes, administration during the current depressive episode.

[0029] As used in the context of this invention, unless otherwise stated, the term "therapeutic effective amount" should mean the amount of an active compound or pharmaceutical ingredient that elicits a biological or clinical response in humans sought by a researcher, physician, or other clinician, including relief of signs and / or symptoms of the disease, disorder, or impairment being treated.

[0030] "Clinical response" includes, but is not limited to, improvement in rating scales. These scales assess (i) aspects of social / emotional withdrawal or alienation and / or (ii) aspects of mental or neurological disorders and / or (iii) medical conditions leading to the associated mental or neurological disorder and / or (iv) sleep.

[0031] The severity of a disease and changes in severity can be assessed using the Clinical Global Impression (CGI) rating scale, which measures symptom severity, treatment response, and treatment efficacy.

[0032] The CGI rating scale was developed to provide clinicians with a brief, independent assessment of their perceptions of patients’ overall functioning before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0033] CGI Severity (CGI-S) is based on a question that clinicians must answer: “Given your overall clinical experience with this particular population, how severe is the patient’s current psychosis?” It is assessed using the following seven-point scale: 1 = Normal, no symptoms at all; 2 = Borderline psychosis; 3 = Mild symptoms; 4 = Moderate symptoms; 5 = Severe symptoms; 6 = Severe symptoms; 7 = Most severe symptoms.

[0034] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0035] Clinical response can be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the invention, a decrease in the CGI-S score means a reduction of at least 1 point. Preferably, the CGI-S score decreases by at least 2 points and / or drops to 0 points. Particularly preferably, the CGI-S score decreases by at least 3 points and / or drops to 0 points.

[0036] Alternatively, CGI-I (CGI-I) can be used to assess treatment success, and its format is equally simple. After treatment, the clinician compares the patient's overall clinical condition to their pre-treatment condition (the so-called baseline). Again, only one question is assessed using a seven-point scale: "Compared to the patient's condition at admission (before starting medication), the patient's condition: 1 = Very significant improvement since treatment began; 2 = Significant improvement; 3 = Slight improvement; 4 = No change from baseline (at the start of treatment); 5 = Slight deterioration; 6 = Significant deterioration; 7 = Very significant deterioration since treatment began."

[0037] The Patient Global Impression Scale (PGI), also known as the Subject Global Impression (SGI), is the counterpart to the Clinical Global Impression Scale (CGI). It consists of a CGI-based, patient-specific item. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0038] Individual items and sub-combinations of individual items from the scales described in this article can be used to assess specific disease aspects.

[0039] As used in the context of this invention, unless otherwise stated, the term "application" (or "administration") shall mean the introduction of a certain amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient via any route. The active compound may be administered intravenously, intramuscularly, or subcutaneously.

[0040] As used in the context of this invention, unless otherwise stated, the terms "dose," "dosage," and "dosage amount" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosing regimen" (or "administration regimen") shall mean a defined sequence of single or multiple administrations.

[0041] Social / emotional withdrawal or alienation

[0042] Symptoms such as anhedonia, emotional withdrawal, and emotional apathy are categorized in this article as social / emotional withdrawal or alienation. Reduced social engagement is another aspect associated with social / emotional withdrawal or alienation. Anhedonia refers to the inability to experience pleasure. If the patient's subjective ability to experience pleasure in daily activities is not reduced, then the patient does not suffer from anhedonia. Anhedonia is mild if the pleasure derived from normally pleasurable activities is slightly reduced; moderate if the pleasure derived from normally pleasurable activities is significantly reduced, or if some pleasure derived from isolated activities is retained; or severe if pleasure is completely absent.

[0043] Anhedonia includes both consumptive (or liking) and anticipatory (or wanting) components. Consumptive pleasure refers to the "present" pleasure experienced by a subject when directly engaging in a pleasurable activity, while anticipatory pleasure refers to the pleasurable experience associated with future activities.

[0044] Affective apathy is a subjective feeling of a reduction in the intensity or range of sensations or emotions. If no reduction in the intensity or range of sensations or emotions is felt, the subject does not exhibit affective apathy. Mild affective apathy is characterized by a slight reduction in the range of emotions, or a temporary decrease in the range or intensity of sensations; moderate affective apathy is characterized by a significant reduction in the range or intensity of sensations, but with some emotion retained, such as the inability to cry; and severe affective apathy is characterized by a marked and generalized reduction in the range of emotions, or the inability to experience normal emotions.

[0045] Emotional withdrawal or alienation refers to the inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes items related to emotional withdrawal, characterized by a subject's deficit in expressing emotions during the interview. According to the description of these BPRS items, if there is no lack of emotional engagement, manifested as occasional unresponsive comments, occasional absent-mindedness, or a stiff smile, but spontaneous interaction with the interviewer most of the time, then there is no emotional withdrawal. If there is a lack of emotional engagement, manifested as noticeably unresponsive comments, absent-mindedness, or lack of enthusiasm, but responsiveness when the interviewer approaches, then there is mild emotional withdrawal. If there is no emotional contact for most of the interview, because the subject does not respond in detail, does not make eye contact, seems unconcerned about whether the interviewer is listening, or may be engrossed in psychiatric material, then emotional withdrawal is moderate to severe. Furthermore, if there is no emotional contact for most of the interview, then emotional withdrawal is moderate to severe. If the subject actively avoids emotional engagement, or if the subject frequently does not respond, responds with yes / no answers, or only with minimal emotional response, then a severe form is present. Emotional withdrawal is considered severe if the subject consistently avoids emotional engagement, does not respond, responds with yes / no answers, may leave during the interview, or does not respond at all.

[0046] Decreased social participation is defined by subjective reports of reduced social and interpersonal participation or interaction. If no reports of decreased social and interpersonal participation or interaction are received, then there is no decrease in social participation. A slight decrease in social participation without impairment of social or interpersonal function is considered mild; a significant decrease in social participation accompanied by functional sequelae, such as avoidance of some social engagement or conversation, is considered moderate; and a significant decrease in social interaction or avoidance of almost all forms of social contact, such as refusing to answer the phone or see friends or family, is considered severe.

[0047] Social / emotional withdrawal or alienation may be associated with mental disorders, neurological disorders, or some other medical conditions.

[0048] Mental or neurological disorders that lead to or are associated with social / emotional withdrawal or alienation include disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar I and bipolar II; postpartum depression (PPD); seasonal affective disorder (SAD); 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 physical dysmorphic disorder (BDD); and post-traumatic stress disorder. PTSD; pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); Lewy body dementia (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0049] Social / emotional withdrawal or alienation can also occur in patients with sleep disorders (such as insomnia).

[0050] Social / emotional withdrawal or alienation can also occur in patients with medical conditions that lead to related mental or neurological disorders, including traumatic brain injury (TBI).

[0051] Measuring social / emotional withdrawal or alienation

[0052] Social / emotional withdrawal or alienation, or its individual aspects such as anhedonia, emotional withdrawal, and emotional coldness, can be evaluated using various tools (such as questionnaires or scales).

[0053] The questionnaire assesses a patient's mental state based on observations by the patient, caregivers, or the clinician responsible for the questionnaire. Questionnaires used to assess whether a patient suffers from a specific mental or neurological disorder may include items related to social / emotional withdrawal or alienation.

[0054] The Snaes-Hamilton Anhedonia Scale (SHAPS) is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover areas including social interaction, food and drink, sensory experiences, and interests / recreations. A score of 2 or less constitutes a “normal” score, while a score of 3 or higher is defined as an “abnormal” score. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Any “disagree” response is scored one point, and any “agree” response is scored 0 points. Therefore, the final score range is 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression, but it is also frequently used to assess anhedonia in other patient populations.

[0055] In principle, SHAPS uses 14 hypothetical items to measure the hedonistic tone of the past few days. However, due to the hypothetical nature of the items, a shorter recall period can also be applied to earlier assessment points.

[0056] Alternatively, the Dimensional Anhedonia Rating Scale (DARS) can be used to assess anhedonia, which measures interest, motivation, effort, and consumptive pleasure in four domains: hobbies, food / drinks, social activities, and sensory experiences. The scale includes 17 items assessing current anhedonia. The DARS uses a five-point Likert scale, ranging from 0 (absolutely none) to 4 (very much), with higher values ​​indicating less anhedonia. Total scores for all items range from 0 to 68. For the four hedonic domains—hobbies (four items, total score 0-16), food / drinks (four items, total score 0-16), social activities (four items, total score 0-16), and sensory experiences (five items, total score 0-20)—participants are asked to provide two or three of their favorite examples.

[0057] The DSM-5 Personality Inventory (PID-5) for adults is a 220-item self-assessment scale for personality traits in adults aged 18 and older. It assesses 25 personality trait aspects, including anhedonia, anxiety, attention-seeking, coldness, deceit, depression, inattention, eccentricity, emotional instability, grandiosity, hostility, impulsivity, avoidance of intimacy, irresponsibility, manipulativeness, perceptual dissonance, obstinacy, emotionally restricted, rigid perfectionism, risk-taking, dissociative insecurity, conformity, suspiciousness, unusual beliefs and experiences, and withdrawal. Each trait aspect consists of 4 to 14 items.

[0058] The anhedonia trait includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (reverse rating items are marked with the letter "R"); the withdrawal trait includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186; and the avoidance of intimacy trait includes items 89, 97R, 108, 120, 145, and 203. These three trait aspects can be combined to produce a broader trait domain, designated as alienation.

[0059] The measurements were completed by the individual before their visit to the clinician. Each item required the individual to rate how well the item described him or her overall character.

[0060] Each item in the measurement was rated using a 4-point scale. The response categories for the items were: 0 = very wrong or often wrong; 1 = sometimes wrong or somewhat wrong; 2 = sometimes right or somewhat right; 3 = very right or often right. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, these items were back-coded before being included in the scale scoring calculation.

[0061] The scores for items within each trait aspect should be summed and entered into the appropriate raw aspect rating box. Additionally, clinicians are required to calculate and use the average score for each aspect and domain. The average score reduces the total score and the score for each domain to a 4-point scale, allowing clinicians to consider an individual's personality dysfunction relative to observed norms. The average aspect score is calculated by dividing the raw aspect score by the number of items in the aspect (e.g., if all items in the "anhedonia" aspect are rated "sometimes or somewhat correct," the average aspect score would be 16 / 8 = 2, indicating moderate anhedonia). The average domain score is calculated by summing the scores of the three aspects that primarily contribute to a particular domain and then averaging them. For example, if the average aspect scores for anhedonia, avoidance of intimacy, and withdrawal (a scale primarily indexing alienation) are all 2, the sum of these scores would be 6, and the average domain score would be 6 / 3 = 2. A higher average score indicates a more severe dysfunction in a particular personality trait aspect or domain.

[0062] High scores in a particular area or domain may indicate that the individual receiving care has significant and problematic areas that may require further evaluation, treatment, and follow-up.

[0063] Scales for assessing mental and neurological disorders

[0064] Several scales have been developed to assess the severity of mental or neurological disorders. These scales are based on tests that can be self-administered or administered by a clinician.

[0065] The scales that can be used according to the invention include those known in the art for diagnosing and / or monitoring mental or neurological disorders, which are discussed in more detail below.

[0066] Treatment outcomes are assessed using one or more indices or scales at one or more time points after the completion of the treatment process.

[0067] Assessment can be performed after the acute psychedelic experience has subsided. The appropriate time for early assessment is typically about 2 to 3 hours after the last administration. Early assessment can usually be performed, for example, about 2 or 3 hours after the last administration.

[0068] However, the impact of the sleep disorder can be assessed as early as the second day after treatment (i.e., day 1), giving the treated patient the opportunity to sleep for at least one night.

[0069] Therefore, the assessment on day 1 or day 1 means the assessment on the second day after application. The assessment shall be performed no earlier than 12 hours after the last application, and in any event no earlier than the night after the last application, and no later than 36 hours after the last application. An assessment may be performed approximately 24 hours later.

[0070] The assessment on day 7 or day 7 refers to an assessment performed on the seventh day after application (day 0 is the day of application). A similar definition applies to other assessment times measured in days.

[0071] When assessing clinical response at an early time point after drug administration (e.g., 2 hours), such as when using one of the scales described to assess the severity of a mental or neurological disorder, the endpoint can be reasonably modified based on the endpoint developed for a longer recall period (e.g., the MADRS is typically 7 days). This could be done by changing the MADRS recall period to 2 hours and carrying over the sleep item from the baseline record prior to drug administration. Unless a recall period is specifically specified, this also applies to any other scales used herein.

[0072] The considerations outlined apply to earlier time points because, on the one hand, the patient’s condition before treatment should have as little influence as possible on any scores recorded after treatment in order to assess clinical response, and on the other hand, sleep items cannot be assessed 2 hours after medication administration.

[0073] At a later point in time, such as on day 1 or later, an appropriate recall period (if necessary) can often be used to assess all items of the relevant scales used to assess clinical response, so that no pre-treatment scores need to be carried forward.

[0074] Resting state: network and social / emotional withdrawal or alienation

[0075] Functional magnetic resonance imaging (fMRI) can be used to study brain processes. Brain activity is related to blood flow, and the temporal correlation of spontaneous oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0076] Functional imaging of the brain was obtained over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distribution areas with correlated and negatively correlated fluctuations.

[0077] In this way, resting-state fMRI can be used to characterize large-scale functional networks, known as resting-state networks (RSNs), which are a group of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize networks of brain regions with coherent patterns of signal variation, which are referred to as resting-state networks (RSNs).

[0078] Based primarily on the spatial similarity between resting-state networks and activation patterns observed in task-based fMRI experiments, different resting-state networks have been identified and named.

[0079] Therefore, resting-state fMRI can be used to assess the brain's intrinsic functional organization. Resting-state networks are characterized by aspects of attention, memory, cognitive control, default modes, motor and sensory systems.

[0080] The resting-state network (RSN) has been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in a variety of disease states. Such disease states (including certain forms of social / emotional withdrawal or alienation) are associated with altered functional connectivity within a specific resting-state network and / or between one or more regions in one or more additional resting-state networks.

[0081] Alterations in the RSN (Reactive Sense Network) also involve anhedonia, a key aspect of social / emotional withdrawal or alienation. More specifically, anhedonia is associated with hyperconnectivity in the visual network and expansion of the visual network, dorsal attentional network (DAN), and default mode network (DMN). Anhedonia also involves decreased connectivity between the DMN, salience, DAN, somatic motor, and visual networks.

[0082] Furthermore, emotional alienation in adult psychosis is associated with structural abnormalities in the dorsal lateral prefrontal cortex (DMN). Because the dorsal DMN has functions related to psychosis, it is of particular interest in the development of psychosis. Specifically, the dorsal DMN and the areas it connects to (the medial prefrontal cortex and posterior cingulate cortex (PCC)) support emotional, social, and moral processing. In adult psychosis, microstructural abnormalities within the dorsal DMN are associated with emotional and interpersonal differences that define the aforementioned disorders.

[0083] Therefore, compared with age-matched healthy controls, patients with social / emotional withdrawal or alienation exhibit altered functional connectivity within and / or between the RSNs. Changes were observed within and / or between the DMN, salience, DAN, somatic motor, and visual networks.

[0084] In many cases, RSN involving social / emotional withdrawal or alienation is influenced by mental or neurological disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar I and bipolar II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); and 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 the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); Lewy body dementia (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).

[0085] Resting-state networks involving social / emotional withdrawal or alienation can also be affected by mental or neurological disorders, which are the result of certain medical health conditions such as traumatic brain injury (TBI).

[0086] Resting-state networks involving social / emotional withdrawal or alienation are also affected by sleep disturbances such as insomnia. In fact, social / emotional withdrawal or alienation is associated with sleep impairment.

[0087] Treatment of social / emotional withdrawal or alienation and mental or neurological disorders

[0088] According to the present invention, social / emotional withdrawal or alienation occurring in patients suffering from mental disorders or neurological disorders can be treated. Furthermore, social / emotional withdrawal or alienation occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

[0089] In patients suffering from social / emotional withdrawal or alienation associated with another disorder detailed above, treatment of social / emotional withdrawal or alienation according to the invention resulted in improvement of the disorder associated with social / emotional withdrawal or alienation.

[0090] The treatment according to the invention is performed by applying 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0091] Administration of 5-MeO-DMT to a patient disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to a reset of pathologically malfunctioning connections when the network reconnects. New, healthy functional connections are then established, and their effects are lasting.

[0092] Therefore, according to the present invention, influencing these networks through the therapy described herein will result in an improvement in social / emotional withdrawal or alienation, and if the treated patient suffers from a mental or neurological disorder, the disorder will also be improved; if the treated patient suffers from a sleep disorder (e.g., insomnia), the sleep disorder (e.g., insomnia) will also be improved.

[0093] To further support the clinical application of 5-MeO-DMT in patients suffering from social / emotional withdrawal or alienation, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients being treated for mental illness and noted a particular improvement in social / emotional withdrawal or alienation, which is also commonly observed in patients with other disorders.

[0094] This data comes from a recently completed clinical trial that used 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations and designs made in the trial were relevant to the treatment of other disorders associated with social / emotional withdrawal or alienation.

[0095] In clinical trials, 5-MeO-DMT was administered via inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of this invention, it is of interest to receive a single 12 mg dose and to receive an intraday individualized dosing regimen (IDR) that allows for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day based on the intensity of the patient's reported psychedelic experience.

[0096] The collected data included assessments of treated patients on several scales, including the Montgomery-Asperger Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the trial focused on demonstrating therapeutic efficacy through improvements in overall MADRS scores, the inventors focused on the items that make up the various rating scales and noted that specific sub-rating items (such as those associated with social / emotional withdrawal or alienation) were associated with other disorders in which social / emotional withdrawal or alienation was based on similar altered functional connectivity within and / or between the default mode network, salience network, dorsal attention network, somatomotor network, and visual network.

[0097] Multiple patients in the recruited cohort showed significant improvement, a result that confirms the inventors’ finding that 5-MeO-DMT is a suitable compound for treating patients with these symptoms.

[0098] More specifically, one aspect that can be treated by applying 5-MeO-DMT is social / emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and / or emotional apathy. Another aspect is reduced social engagement. 5-MeO-DMT can be applied to patients to reduce or eliminate said social / emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and / or emotional apathy. Additionally, reduced social engagement is improved, i.e., reduced or eliminated.

[0099] The MADRS item “loss of sensation”, which is particularly associated with social / emotional withdrawal or alienation, represents a subjective experience of reduced interest in the surrounding environment or activities that would normally bring pleasure. It also indicates a reduced ability to make adequate emotional responses to the environment or people.

[0100] A score of 0 indicates normal interest in one's surroundings and other people, while a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 indicates a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional numbness, an inability to feel anger, grief, or pleasure, and a complete or even painful loss of affection for loved ones.

[0101] In the study group receiving the individualized dosing regimen, all eight patients had a total MADRS score of 36 for "sensory loss" at baseline. Two hours later, the score decreased to 12, corresponding to a 24-point or 67% improvement. On day 1 post-treatment, the score decreased to 2, corresponding to a 34-point or 94% improvement. On day 7 post-treatment, the score decreased to 6, corresponding to a 30-point or 83% improvement.

[0102] In the 12mg group, the total MADRS score for "sensory loss" in all 4 patients was 16 at baseline. Two hours later, the score decreased to 9, corresponding to a 7-point or 44% improvement. On day 1 post-treatment, the score decreased to 1, corresponding to a 15-point or 94% improvement. On day 7 post-treatment, the score decreased to 1, corresponding to a 15-point or 94% improvement.

[0103] The items in the BPRS scale that are particularly associated with social / emotional withdrawal or alienation are "sensory loss" and "emotional blunting".

[0104] The BPRS program's "emotional withdrawal" metric is associated with patients' lack of emotional engagement in interview settings. Possible scoring methods include:

[0105] 1- Emotional withdrawal.

[0106] 2- Very mild. Lack of emotional engagement, manifested as occasional inability to make mutual comments, occasional preoccupation, or unnatural laughter, but most of the time spontaneous interaction with the interviewer.

[0107] 3- Mild. Lack of emotional investment, manifested as a marked inability to make mutual comments, appearing preoccupied or unenthusiastic, but responding when the interviewer approaches.

[0108] 4- Moderate. Emotional exchange is rare in interviews because subjects do not respond in detail, do not make eye contact, do not seem to care whether the interviewer is listening, or may be completely absorbed in psychotic material.

[0109] 5 - Moderate to severe. Same as "4", but with no emotional exchange for most of the interview.

[0110] 6 - Severe. Actively avoids emotional involvement. Often does not respond or responds with yes / no answers (not just due to paranoia). Or responds with minimal emotional response.

[0111] 7 - Profound. Consistently avoids emotional engagement. Does not respond or responds with a yes / no answer (not solely due to paranoia). May leave during the interview or simply not respond at all.

[0112] The total score for “emotional withdrawal” in the BPRS program was 13 at baseline. After 3 hours, the score decreased to 8, corresponding to a 5-point or 38% improvement. On day 1 post-treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement. On day 7 post-treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement.

[0113] In the 12mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. On day 1 post-treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement. On day 7 post-treatment, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0114] The BPRS project's "emotional blunting" involves a limited range of emotional expression through facial expressions, voice, and gestures, as well as noticeable indifference or apathy, even when discussing distressing topics. Possible scoring options are:

[0115] 1- Lack of emotional sluggishness.

[0116] 2 - Very mild. Emotional range is slightly suppressed or reserved, but appropriate facial expressions and tone of voice are displayed within normal limits.

[0117] 3- Mild. The emotional range is generally reduced, suppressed, or reserved, with little spontaneous and appropriate emotional response. The tone is somewhat monotonous.

[0118] 4- Moderate. A significantly reduced range of emotions; with very few exceptions, the patient shows no emotion, smiles, or responds to distressing topics. The tone of voice is monotonous, or spontaneous movements are significantly reduced. After expressing emotion or gestures, the patient usually reverts to emotional indifference.

[0119] 5 - Moderate to severe. The emotional range is very small; the patient does not express emotion, smile, or respond to distressing topics. Aside from a few gestures, facial expressions are infrequent. The tone of voice is monotonous most of the time.

[0120] 6 - Severe. Very limited range of emotions or expression. Speech and gestures are mostly mechanical. Facial expressions are unchanging. Tone of voice is mostly monotonous.

[0121] 7 - Very severe. Almost no emotional range or expressive ability; movements are stiff. The tone of voice is consistently monotonous.

[0122] The total score for “Affective Distress” in the BPRS program was 15 at baseline. After 3 hours, the score decreased to 11, corresponding to a 4-point or 27% improvement. On day 1 post-treatment, the score decreased to 8, corresponding to a 7-point or 47% improvement. On day 7 post-treatment, the score decreased to 8, corresponding to a 7-point or 47% improvement.

[0123] In the 12mg group, the total score for the BPRS item "Affective Distress" was 11 at baseline. After 3 hours, the score decreased to 8, corresponding to a 3-point or 27% improvement. On day 1 post-treatment, the score decreased to 6, corresponding to a 5-point or 45% improvement. On day 7 post-treatment, the score decreased to 5, corresponding to a 6-point or 55% improvement.

[0124] Therefore, scores on scale items particularly associated with social / emotional withdrawal or alienation, namely “Asynchronous Sensory Reduction Scales” (MADRS), “Affective Withdrawal Scales” (BPRS), and “Affective Desensitization Scales” (BPRS), were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat patients with social / emotional withdrawal or alienation, especially those who also suffer from mental disorders, neurological disorders, or sleep disturbances (such as insomnia).

[0125] Therefore, according to the present invention, treatment of patients suffering from social / emotional withdrawal or alienation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates social / emotional withdrawal or alienation.

[0126] Active agent

[0127] The above discussion shows that social / emotional withdrawal or alienation itself can have a significant disease burden and requires appropriate treatment.

[0128] The inventors believe that carefully selected hallucinogens may lead to treatments that improve important aspects of social / emotional withdrawal or alienation, and may result in overall improvement of the condition.

[0129] A group of hallucinogens contains compounds that bind to serotonin (5-HT) receptors, also known as serotonin receptors (described as a family of seven with several subtypes, 5-HT1 to 5-HT7). Examples include lysergic acid diacetamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonin-like agents are often referred to as "psychedelics," highlighting their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, changes in time and space, psychic experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are negligible.

[0130] From a chemical perspective, serotonin psychedelics are either phenylalkylamines or indoleamines. Indoleamines are further divided into two subsets: ergoline and tryptamines, the latter of which are derived from tryptamines.

[0131] Various serotonin psychedelics have different binding affinities and activation efficacies for various serotonin receptors (especially 5-HT1A, 5-HT2A, and 5-HT2C), and their activity can also be modulated through interactions with other targets (such as monoamine transporters and trace amine-associated receptors).

[0132] Recent studies on the use of serotonin-containing psychedelic drugs (such as LSD, psilocybin, and DMT (using ayahuasca, a shamanic elixir containing DMT) in certain mental disorders suggest that these compounds could offer alternative treatments for some currently available mental disorders. However, there are reports that these compounds may induce mania in patients with depressive symptoms, which could hinder their clinical use.

[0133] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported a case of a patient experiencing a manic episode after taking LSD or an LSD analogue. The patient presented with acute LSD intoxication symptoms, which were relieved, but a typical psychotic manic episode occurred 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. BipolarDisorders 23(4): 1-3) reported a manic episode following self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP and Jose M Smith, JM, 2015. Switch to mania afterayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3: 4) reported a case report of a man with bipolar disorder who turned manic after drinking ayahuasca (a beverage containing DMT).

[0134] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0135] The inventors believe that, in order to avoid inducing mania or mild mania, or at least reduce the risk of inducing mania or mild mania, it is necessary to properly select the compound to be administered and preferably administer it according to a specific dosing regimen.

[0136] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic drug of particular interest for therapeutic purposes. 5-MeO-DMT possesses unique pharmacological properties that distinguish it from other psychedelic drug compounds.

[0137] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts on 5-HT1A and 5-HT2A receptors, and has a higher affinity for the 5-HT1A receptor subtype compared to other classic psychedelic drugs.

[0138] The dephosphorylated psilocin (the dephosphorylated form of psilocin formed after psilocin uptake), DMT, and the inhibitory constants (Ka) of 5-HT1A receptors in the hippocampus of post-mortem human brains, as further detailed in the Examples section below, are described. i The inhibitory constants (K2) were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibited high affinity for the 5-HT1A receptor, while dephosphorylated psilocybin and DMT showed moderate affinity. The inhibitory constants (K2) of dephosphorylated psilocybin, DMT, and 5-MeO-DMT at the 5-HT2A receptor located in the frontal cortex of the post-mortem human brain were... i The values ​​were 37, 117, and 122 nM, respectively. Therefore, dephosphorylated psilocybin showed moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT showed relatively weak affinity.

[0139] Compared to the other previously mentioned psychoactive compounds, 5-MeO-DMT exhibits enhanced affinity for the 5-HT1A receptor, in which case it acts as a potent agonist. In the cases of dephosphorylated psilocybin and DMT, the contribution of 5-HT2A binding is increased compared to 5-MeO-DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Therefore, compared to the other two compounds, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared to 5-HT2A binding.

[0140] It has been reported that 5-HT1A agonists reduce impulsivity and aggression, while 5-HT2A agonists can cause a short-term increase in these same traits. Furthermore, the dopamine system is associated with mania, and an increase in dopamine drive is linked to mania. Compared to 5-MeO-DMT, LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors.

[0141] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using the dosing regimen described herein without posing a significant risk of inducing mania or hypomania in patients with mental or neurological disorders, including disorders characterized by depressive episodes such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I and bipolar II; psychotic disorders such as schizophrenia; or personality disorders such as schizotypal personality disorder. Patients with such mental or neurological disorders and treated according to the present invention will not experience treatment-induced mania or hypomania.

[0142] It is also noteworthy that reports of mania or hypomania induced by treatments involving the use of psychoactive substances appear to indicate the use of large amounts of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0143] The inventors’ 5-MeO-DMT up-titration method significantly reduces the risk of overdose and the likelihood of associated adverse events.

[0144] Furthermore, it has been reported that antidepressants can 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, recently completed clinical trials of 5-MeO-DMT in TRD patients have not shown evidence of inducing hypomania.

[0145] 5-MeO-DMT can induce effervescent experiences (i.e., experiences characterized by a shift in emotional perspective, described as “loss of self”, typically ending in an overwhelming sense of “oneness with the universe”) more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to several hours for, for example, oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved treatment profile, which can be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0146] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor as a radioligand... 3 H]LSD and serotonin were used to estimate nonspecific binding, and K was measured. i It is 2.3 nM.

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

[0148] 5-HT7 receptors play a role in neurogenesis, synapsis, and dendritic spine formation. Among other things, they are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociceptive sensation.

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

[0150] The suprachiasmatic nucleus (SNU) is the central pacemaker of the circadian rhythm system. It coordinates the diurnal rhythms of various brain regions. Disruptions in this coordination can lead to disease states, particularly those involving sleep disorders. In patients with sleep disorders, resting-state functional connectivity analysis revealed altered functional connectivity between the SNU and regions within the default mode network.

[0151] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the receptor's role in regulating the sleep / wake cycle. The inventors believe this allows for the treatment of patients with sleep disorders via 5-MeO-DMT that acts on the receptor.

[0152] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor (which acts as a mediator for the pharmacological action of 5-MeO-DMT) involves the "resetting" of functional connectivity in networks and neuroplasticity effects, which may help 5-MeO-DMT to play a beneficial role in the treatment of patients with sleep disorders.

[0153] The inventors further believe that the binding of 5-MeO-DMT to both the 5-HT7 and 5-HT1A receptors (as two mediators in the action of 5-MeO-DMT) involves a "reset" of functional connectivity in the network and neuroplasticity effects, allowing for beneficial effects in patients with other symptoms or disorders, such as cognitive impairment, anxiety, psychomotor retardation, negative thinking, or sleep disturbances. Clinical results from the studies cited in this article support this.

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

[0155] 5-MeO-DMT is mainly inactivated via the monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzyme.

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

[0157] Pharmacokinetic analysis of inhaled 5-MeO-DMT showed a very rapid decline in plasma concentration. At 10 minutes post-administration, the concentration decreased to 10% or less of Cmax; after 2 hours, the concentration was 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detectable in plasma. This applied to the full dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administrations over a timeframe of 1 to 4 hours. Up-titration as disclosed herein does not lead to accumulation and therefore does not result in higher plasma concentrations, such as at 10 minutes, 2 hours, or 3 hours post-administration.

[0158] The properties of 5-MeO-DMT make the compound particularly suitable for treating social / emotional withdrawal or alienation, especially for patients suffering from mental or neurological disorders.

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

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

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

[0162] The deuterated form of 5-MeO-DMT is a form with a deuterium content higher than that expected based on the natural abundance of the isotope.

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

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

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

[0166] The methods for preparing these compounds are known in the art.

[0167] According to 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, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used.

[0168] Furthermore, according to the present invention, the amounts of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used are equimolar with the amounts of the corresponding non-deuterated forms.

[0169] According to the present invention, a prodrug of 5-MeO-DMT and a pharmaceutically acceptable salt of such a prodrug can also be used. Such a prodrug of 5-MeO-DMT can be metabolized into 5-MeO-DMT. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, it can be replaced by a 5-MeO-DMT prodrug or a salt thereof.

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

[0171] A suitable example of an organic moiety is C(O)OR 1 -C(O)R 2 -CH(R) 3 )OR 4 -C(O)OCH(R) 3 )OC(O)R 4 -C(O)OCH(R) 3 )OC(O)OR 4 -CH(R) 3 )C(O)R 4 -CH(R) 3 )OC(O)R 4 -CH(R) 3 )OC(O)OR 4 , where R 1 、R 2 、R 3 and R 4 Each of them is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

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

[0173] Prodrugs, especially those with the above-described structures, can also be used in pharmaceutically acceptable salt form.

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

[0175] The methods for preparing prodrugs, as discussed herein, are known in the art.

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

[0177] Furthermore, according to the present invention, the amounts of the 5-MeO-DMT prodrug and the salt of the 5-MeO-DMT prodrug are equimolar with the amounts of the corresponding non-prodrug forms.

[0178] Application mode

[0179] Therapeutic doses of 5-MeO-DMT are administered via intravenous, intramuscular, or subcutaneous administration. These routes ensure rapid onset of action. The preferred route of administration is intravenous, i.e., intravenous injection.

[0180] 5-MeO-DMT may be used in the form of a pharmaceutically acceptable salt, preferably hydrobromide, or in the form of a formulation administered by injection, examples of excipients and mediators of such formulations are known in the art.

[0181] Dosage regimen

[0182] The present invention also provides dosage ranges, specific dosages, administration regimens (application regimens), and appropriate routes of administration.

[0183] This invention is partly based on the inventors’ conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which drives therapeutic benefits of 5-MeO-DMT or a pharmaceutically acceptable salt thereof for patients suffering from social / emotional withdrawal or alienation, particularly one or more aspects as defined above, said therapeutic benefits either causally or at least as alternative behavioral markers of potential unknown therapeutic mechanisms.

[0184] Therefore, achieving peak experience more quickly in a larger proportion of patients and having better repeatability in individual patients will lead to a better treatment profile compared to previously tested psychedelics, dosing regimens, and routes of administration.

[0185] Furthermore, this invention relies on the short duration of action and absence of associated tolerability of 5-MeO-DMT (i.e., no diminishing or disappearance of psychedelic effects after reapplication) as the basis for a dosing regimen that enables frequent reapplication (such as more than once daily or once daily), designed to increase the incidence of peak experiences and thus increase therapeutic benefits. Such repeated administration over a short period also allows for intra-individual dose optimization, which reduces the risk of overdose that could otherwise lead to physical side effects such as serotonin syndrome, negative psychological reactions (such as flashbacks at later points in time), induction of mania or hypomania, or psychedelic experiences with little or no meaningful memory of altered states (so-called "albinism"). Moreover, starting at a low dose allows patients to become familiar with general psychedelic experiences and prepares them for more intense symptoms at higher doses, which will positively impact the experience at higher doses. Furthermore, the prospect of being able to start treatment at a low dose will increase patient acceptance of the treatment and improve overall adherence at the patient population level.

[0186] Frequent reapplication of serotonin psychedelics can increase the frequency and repeatability of peak experiences, and improve treatment efficacy, reduce side effects, and increase compliance, which may not be possible with other psychedelics because the psychedelic effects take effect later and last longer, and tolerance develops rapidly (i.e., the psychedelic effects diminish or disappear after reapplication), and this tolerance may last for several days.

[0187] Patients suffering from social / emotional withdrawal or alienation as defined herein, who are treated with 5-MeO-DMT or its pharmaceutically acceptable salts.

[0188] In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, meaning the patient does not receive any other social / emotional withdrawal or alienation treatment.

[0189] The dosage range of 5-MeO-DMT for use in patients with social / emotional withdrawal or alienation as defined herein is from about 1 mg to about 10 mg, or any range therewith, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT (such as hydrobromide), the weight of which may be calculated based on the prescribed weight of the free base of 5-MeO-DMT, assuming the use of equimolar amounts. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Note that in this specification, when ranges are listed (such as “about 1 mg to about 10 mg”), the inventors have considered all discrete values ​​within that range, some of which are explicitly mentioned, but not all – this is merely for the purpose of brevity.

[0190] In a preferred embodiment, an improved method of using a therapeutically effective amount of 5-MeO-DMT to treat patients suffering from social / emotional withdrawal or alienation as defined herein includes the appearance of a clinical response no later than about 2 hours after administration of 5-MeO-DMT.

[0191] In a preferred embodiment, an improved method of treating patients with social / emotional withdrawal or alienation as defined herein using a therapeutically effective amount of 5-MeO-DMT includes a sustained clinical response, including a clinical response that appears no later than about 2 hours after administration of 5-MeO-DMT and persists 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.

[0192] In a preferred embodiment, an improved method of using a therapeutically effective amount of 5-MeO-DMT to treat patients suffering from social / emotional withdrawal or alienation as defined herein includes administering more than a single dose of 5-MeO-DMT.

[0193] In a preferred embodiment, the patient is given more than a single dose of 5-MeO-DMT in one or more treatment blocks, each block consisting of 2 to 7 administrations, with an interval of not less than about 1 hour and not more than about 24 hours between administrations within each treatment block, and an interval of not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0194] In an even more preferred embodiment, the patient is given more than a single dose of 5-MeO-DMT in one or more treatment blocks, each block consisting of 1 to 3 administrations, with an interval of about 24 hours between each administration within each treatment block, and an interval of not less than about 6 days between the end of one treatment block and the start of the next treatment block.

[0195] In the most preferred embodiment, the patient is given more than a single dose of 5-MeO-DMT in one or more treatment blocks, each block consisting of 1 to 3 administrations, with an interval of about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and the interval between the end of one treatment block and the start of the next treatment block is not less than about 6 days.

[0196] In the implementation scheme, the dose of 5-MeO-DMT administered to an individual patient in each application and in each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0197] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration within each treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within each treatment block until reaching 10 mg, or the earlier of all administrations within that treatment block.

[0198] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration within each treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that it is not appropriate to further increase the dose based on observed side effects.

[0199] For embodiments involving subsequent dose increases, the dose of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dose of the previous administration. For example, if the first administration dose was 1 mg and the dose is increased to 3 mg, the second administration dose is 4 mg unless one of the aforementioned discontinuation criteria has been met. Preferably, the third administration dose is 7 mg.

[0200] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg at the first administration, and then increased to a dose selected from about 4 mg to about 6 mg at the second administration, and to a dose selected from about 7 mg to about 9 mg at the third administration, unless the patient has experienced a peak psychedelic experience in said treatment block or the attending physician determines that further dose increases are not appropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0201] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg at the first administration, and then increased to a dose selected from about 1.5 mg to about 2.5 mg at the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg at the third administration, unless the patient has already experienced a peak psychedelic experience in said treatment block or the attending physician determines that further dose increases are not appropriate based on observed side effects. The useful specific amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0202] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines, based on observed side effects, that further dose increases are not appropriate, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 8 mg because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.

[0203] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 1 mg to about 3 mg. Then, unless the patient has already experienced a peak psychedelic experience within the treatment block or the attending physician determines, based on observed side effects, that further dose increases are not appropriate, the second administration of the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration of the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg. The highest dose in the first treatment block will be used for all subsequent treatment blocks and for administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0204] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 0.5 mg to about 1.5 mg. Then, unless the patient has already experienced a peak psychedelic experience within the treatment block or the attending physician determines, based on observed side effects, that further dose increases are not appropriate, the second administration of the first treatment block will be increased to a dose selected from about 1.5 mg to about 2.5 mg, and the third administration of the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and for administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0205] It should be understood that pharmaceutically acceptable salts of 5-MeO-DMT are preferred for all of the above-described dosing regimens, and assuming the use of equimolar amounts, the appropriate weight of the salt to be administered can be calculated based on the specified weight of the free base.

[0206] According to the present invention, 5-MeO-DMT is preferably not administered together with MAO inhibitors.

[0207] A patient’s “peak psychedelic experience” can be identified by achieving at least 60% of the highest possible score on each of the four subscales (mystery, positive emotion, transcendence of time and space, and ineffable) of the revised Mysterious Experience Questionnaire-30 (MEQ-30) with 30 items (mystery, positive emotion, transcendence of time and space, and ineffable). (As described in Barrett FS, J Psychopharmacol. 2015; 29(11): 1182-90).

[0208] Whether a patient experiences a “peak psychedelic experience” can also be determined by achieving at least 60% of the highest possible score on the Ocean-like Boundless (OBN) dimension of the Altered Consciousness State (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018; 8: 974).

[0209] According to the present invention, whether a patient experiences a “peak psychedelic experience” is preferably identified by achieving a total score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient’s responses to the following three questions from 0 to 100: 1. How intense was the experience; 2. How much was the loss of control; 3. How significant (i.e., profound and important) was the experience?

[0210] Treatment of social / emotional withdrawal or alienation and sleep disorders

[0211] Sleep disorders are conditions that affect the quality, duration, or quality of sleep, whether idiopathic or occurring within the context of a medical condition (e.g., a mental or neurological disorder). Sleep disorders can impair an individual's ability to function normally while awake and are associated with patterns of high negative and low positive affect.

[0212] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increases in sleep depth. During the four to five cycles of normal human sleep each night, non-REM and REM sleep alternate. In the earlier part of the night, non-REM sleep is deeper and takes up a disproportionately large amount of time, especially in the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, and more time in each cycle is allocated to REM sleep.

[0213] Normal, healthy sleep consists of different stages as described above, which occur in a continuous, strictly controlled sequence throughout the night.

[0214] Such strict interruption of control can lead to sleep disorders.

[0215] Common forms of sleep disorders include sleep initiation and maintenance disorders (insomnia), excessive sleepiness (hypersomnia), sleep-wake cycle disorders (circadian rhythm disorders), functional disorders related to sleep, sleep stages, or partial awakening (parasomnia), disorders characterized by breathing disturbances during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related motor disorders). In a broader sense, fatigue can also be considered a sleep disorder.

[0216] Insomnia is a sleep disorder in which patients have difficulty falling asleep or maintaining sleep. Symptoms of insomnia include difficulty falling asleep; frequent awakenings during the night and difficulty falling back asleep; waking up too early in the morning; poor sleep quality; and / or having at least one daytime problem due to poor sleep quality, such as fatigue, drowsiness, mood problems, poor concentration, accidents at work or while driving, etc.

[0217] Excessive sleepiness is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep duration. Sleep intoxication is also a symptom found in patients with excessive sleepiness. The transition from sleep to wakefulness is very difficult. Individuals who have experienced sleep intoxication report feeling confused, disoriented, sluggish, and experiencing recurrent sleep episodes upon waking.

[0218] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances resulting from alterations in an individual's internal circadian rhythm or from inconsistencies between their circadian rhythm and their desired or needed work or social schedules. This asynchrony may be temporary or persistent. Subsequent clinical presentations combine symptoms of insomnia and hypersomnia. Sleep duration is typically shortened and interrupted, performance in the desired awake state is impaired, and a temporary inability to restore a normal sleep schedule is observed.

[0219] Parasomnias refer to various forms of sleep disorders characterized by unusual behavioral or physiological activities (such as sleepwalking or nightmares) experienced before falling asleep, during sleep, or during the wakefulness period between sleep and wakefulness. They vary considerably in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0220] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of respiratory muscles and the brain. These sleep disturbances can have a significant impact on the balance of oxygen and carbon dioxide in sleep and blood, manifesting as chronic snoring, sleep apnea, sleep-related hypoventilation, and / or hypoxemia. In some of these disorders, breathing is also abnormal when awake. Reduced airflow can lead to intermittent hypoxia, accompanied by micro-awakes or wakefulness, resulting in fragmented sleep and excessive daytime sleepiness. Inflammation and endothelial dysfunction may occur, reducing vascular elasticity, increasing blood clotting, and making individuals susceptible to atherosclerosis. Combined with reduced oxygenation, this can lead to heart and brain damage.

[0221] Among sleep-related movement disorders, repetitive, relatively simple, and often stereotyped movements can interfere with sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb tic disorder (PLMD).

[0222] Fatigue describes a state of tiredness that cannot be relieved by rest or sleep. It is a feeling of tiredness, drowsiness, or decreased energy, usually manifested as a weakening or depletion of physical or mental resources, and is characterized by decreased work capacity and reduced efficiency in responding to stimuli. Fatigue is normal after a period of mental or physical exertion, but it can also occur in the absence of such exertion and is a symptom of health conditions.

[0223] Insufficient sleep duration or quality can lead to personality changes and not only exacerbate existing mental illnesses but also trigger their development. Sleep disorders can also lead to social withdrawal, as sleep deprivation increases feelings of loneliness and reduces the desire for social interaction. Short sleep duration increases the probability of mood deficits by 55%. Anhedonia is a key symptom and mechanism by which sleep deprivation affects mood. Furthermore, sleep deprivation can contribute to obesity, diabetes, and heart disease, thus negatively impacting quality of life.

[0224] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatments. If these are unsuccessful, treatment may involve medication or psychotherapy.

[0225] The available treatments were unsuccessful in all patients, possibly due to side effects and / or the need for long-term treatment to achieve the desired therapeutic effect.

[0226] In patients with sleep disorders associated with mental or neurological disorders, known treatments for the mental or neurological disorders do not necessarily improve the sleep disorder.

[0227] For example, sleep disorders are frequently associated with mental disorders such as depression. However, treatment of depression does not necessarily lead to improvement in the accompanying sleep disorders. While most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while others can cause sleep impairment (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).

[0228] To assess sleep, parameters such as sleep duration, sleep structure, sleep latency, and the frequency and duration of wakefulness throughout the night can be measured. Quantitative indicators can be measured using objective methods, including polysomnography, actigraphy, and determination of sleep latency, or through self-report measurements (questionnaires).

[0229] Polysomnography is a technique that requires overnight monitoring of patients in a specialist clinic. Various functions are measured throughout the night, including eye movements, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body posture and movement, snoring, and heart rate.

[0230] Sleep latency can be measured using the Multiple Sleep Latency Test (MSLT). This test provides an objective measure of how long it takes for a person to fall asleep after multiple naps. An average sleep latency of approximately 10 minutes is considered normal; less than 8 minutes indicates a sleep disorder. Accompanying brain activity analysis can help further diagnose the sleep disorder.

[0231] The sleep assessment questionnaire recorded the evaluation of components of sleep quality, such as the perception of sleep depth, difficulty of awakening, and rest after sleep, as well as other factors that may affect sleep quality, such as comorbidities and medication use.

[0232] Qualitative evaluation of the sleep experience is very important because sleep discomfort may persist even when quantitative sleep measurements are normal.

[0233] Questionnaires not only help to quickly and accurately assess complex clinical problems, but they can also help track patient progression. Therefore, patient-completed self-reported sleep questionnaires are an important basis for assessing sleep disorders in clinical practice.

[0234] Various sleep quality indices are known. The following indices include examples of questionnaires assessing general sleep, as well as examples of questionnaires specifically assessing insomnia, excessive sleep, circadian rhythm disorders, and parasomnias. However, this invention is not limited to using specific indices or questionnaires.

[0235] For example, the Sleep Quality Scale (SQS) and the Sleep-50 Questionnaire can be used to assess general sleep quality.

[0236] The Sleep Quality Scale (SQS) is a comprehensive assessment tool that provides a universal and efficient measure of sleep quality suitable for evaluating a wide range of patients and research populations. Individual issues related to daytime symptoms, such as attention problems, difficulty concentrating or memory problems (item 15, "Poor sleep quality makes it difficult for me to think," item 19, "Poor sleep quality causes me to make mistakes at work," item 21, "Poor sleep quality makes me more forgetful," item 22, "Poor sleep quality makes it difficult to concentrate at work"), recovery after sleep, problems falling asleep and maintaining sleep, difficulty waking up, and sleep satisfaction, can be rated from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more severe sleep problems.

[0237] The SLEEP-50 questionnaire consists of 50 items and is designed to screen for various types of sleep disorders in the general population. The scale comprises nine subscales reflecting some of the most common disorders and discomforts associated with sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily functioning. For each item, respondents are given a scale from 1 (“none”) to 4 (“a lot”) and are asked to indicate how well the statement matches their experience in the previous month or another appropriate recall window.

[0238] The questionnaire requires that, in order to diagnose sleep disorders, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the influence subscale must also exceed a certain cutoff point (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005; 3(4): 227-46., Table 4, optimal cut-off values ​​and scoring procedures).

[0239] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below the cutoff value.

[0240] The Pittsburgh Sleep Quality Index is a commonly used questionnaire for assessing sleep disorders. Other tools include the Insomnia Severity Index and the Espie Sleep Disorder Questionnaire.

[0241] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a self-assessment questionnaire containing 19 questions. Respondents are asked to indicate the frequency with which they experienced certain sleep difficulties in the past month or another appropriate memory window.

[0242] Nineteen self-assessment questions assessed a variety of factors associated with sleep quality, including estimates of sleep duration and latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items were divided into seven components: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

[0243] Each component is scored from 0 to 3. The higher the score, the more severe the sleep disorder. Detailed scoring instructions for the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. May 1989; 28(2): 193-213.

[0244] The scores of the seven components are then summed to obtain an overall score, ranging from 0 to 21, where "0" indicates no difficulty and "21" indicates severe difficulty in all areas. A total score cutoff of 5 distinguishes people with poor sleep quality from those with good sleep quality. A total score >5 indicates that the patient has severe difficulty in at least two areas, or moderate difficulty in more than three areas.

[0245] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or below.

[0246] The Insomnia Severity Index (ISI) is a five-item questionnaire that covers subjective sleep quality, symptom severity, subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning (item 3, "To what extent do you feel your sleep problems interfere with your daily functioning (e.g., daytime fatigue, ability to perform work / daily tasks, concentration, memory, mood, etc.)."), how much worse the respondent feels their insomnia is compared to others, and the overall level of distress caused by the sleep problem. Individuals can rate their responses from 0 (= none) to 4 (= very bad); a higher total score corresponds to more severe insomnia. A total score of 0-7 indicates "no clinically significant insomnia", 8-14 indicates "subthreshold insomnia", 15-21 indicates "clinical insomnia (moderate severity)", and 22-28 indicates "clinical insomnia (severe)" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012; Bastien et al. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. SleepMed. July 2001; 2(4): 297-307).

[0247] The typical recall window for ISI is two weeks, but other appropriate recall windows may also be used in this paper.

[0248] Treatment success is indicated by (i) a decrease in score, for example, a decrease of >7 points, especially >8 points; preferably (ii) a decrease in score below the cutoff value for clinically significant insomnia.

[0249] The Sleep Attention Scale (SPS) is a 22-item self-report scale designed to assess daytime cognitive abilities in individuals with insomnia. While researchers often focus on nighttime thoughts and attention when attempting to treat sleep disorders, a growing body of research suggests that daytime beliefs about sleep can be just as important as the experience of insomnia. The SPS assesses two distinct domains: the cognitive and behavioral consequences of poor sleep quality (e.g., negative thoughts and perceptions) and the emotional consequences (e.g., worry and distress). This tool is particularly useful for clinicians attempting to identify and treat the root causes of their patients' sleep problems.

[0250] The Espie Sleep Disorders Questionnaire (SDQ) assesses subjective experiences of insomnia. The SDQ assesses anxiety / excitement, hyperactivity, consequences of insomnia, and inadequate sleep preparation, with particular attention to beliefs about the root causes of sleep problems. Respondents use a five-point scale to indicate how frequently certain statements about insomnia represent their experience. 1 means “never true”, while 5 means “often true”. Higher scores indicate more abnormal beliefs about the causes and related factors of insomnia (A. Shahid et al., ibid.; Espie et al. Insomnias' attributes. psychoometric properties of the Dysfunctional Beliefs and Attitudes about Sleep Scale and the Sleep Disturbance Questionnaire. J Psychosom Res. 2000 Feb; 48(2): 141-8).

[0251] A decrease in the score indicates successful treatment.

[0252] Excessive sleep or hypersomnia can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0253] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asked respondents to rate their likelihood of falling asleep under eight different conditions, representing periods of relative inactivity such as an afternoon nap or sitting in a car stopped in traffic. Respondents used a scale of 0-3 (0 meaning "never sleepy" and 3 meaning "very likely to sleepy") to rate their likelihood of falling asleep. The score ranged from 0 to 24; higher scores indicated greater severity of daytime sleepiness. A cutoff score of 10 indicated a possible clinical presentation of daytime sleepiness (A. Shahid et al., ibid., Johns et al., A new method for measuring daytime sleepiness: the Epworthsleepiness scale. Sleep, Dec. 1991; 14(6): 540-5).

[0254] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 10 or below.

[0255] The Stanford Sleepiness Scale (SSS) is a subjective measure of sleepiness that assesses the level of sleepiness at a specific moment. The scale consists of only one item, requiring respondents to choose one of seven statements that best represents their current perceived level of sleepiness. Sleepiness is assessed using a scale ranging from 1 (= feeling active and energetic; alert; fully awake) to 7 (= almost hallucinating; falling asleep quickly; unable to stay awake) (A. Shahid et al., ibid.; Hoddes et al. The development and use of the Stanford sleepiness scale (SSS). Psychophysiology, 1972, 9, 150).

[0256] A decrease in the score indicates successful treatment.

[0257] Parasomnia can be assessed using the Paris Arousal Disorder Severity Scale (PADSS).

[0258] The Paris Arousal Disorder Severity Scale (PADSS) is a self-rating scale that lists parasomnia behaviors, assesses the frequency of parasomnia behaviors, and includes an evaluation of the consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 1 Jan 2014; 37(1): 127-36).

[0259] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below the cutoff value.

[0260] The Berlin Questionnaire is a commonly used questionnaire for assessing sleep-related breathing disorders (A. Shahid et al., ibid.; Netzer et al., Using the Berlin Questionnaire to identify patients at risk for the sleepapnea syndrome. Ann Intern Med. 1999 Oct 5; 131(7): 485-91). An appropriate recall period can also be selected.

[0261] A decrease in the score indicates successful treatment.

[0262] The commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale (A. Shahid et al., ibid.; 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).

[0263] A decrease in the score can be used to assess the treatment response.

[0264] Fatigue is typically assessed using metrics such as FACES (fatigue, weakness, consciousness, energy, drowsiness).

[0265] The FACES (fatigue, weakness, consciousness, energy, drowsiness) rating scale is a list of 50 items used to differentiate between tiredness, somnolence, and fatigue. Respondents used a scale from 0 ("not at all") to 3 ("intense") to indicate how much they experienced each feeling or energy state during the previous week or another appropriate recall period. The higher the score, the more severe the tiredness or fatigue state, except for items belonging to the energy subscale (A. Shahid et al., ibid.; 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).

[0266] Effective treatment can reduce fatigue and / or exhaustion scores and / or increase energy scores.

[0267] Treatment response can be evaluated using the quantitative measurements described above (such as polysomnography or wrist movement) and / or the questionnaires described above. A significant decrease or increase in the total score, or a significant reduction in the prevalence, frequency, and impact on daily functioning, based on the corresponding sleep scale, indicates improvement in treatment-induced sleep disturbances.

[0268] Common tests that can be used to assess social / emotional withdrawal or alienation or aspects thereof include, for example, the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Disorders of Pleasure Rating Scale (DARS), and the DSM-5 Personality Inventory (PID-5) - Adults.

[0269] To enhance our understanding of pathophysiology and underlying compensatory mechanisms, resting-state fMRI has been widely used in patients with sleep disorders.

[0270] Alterations in the resting state network can be found in insomnia, excessive sleep, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related motor disorders.

[0271] In insomnia patients, functional connectivity impairments have been observed within the default mode network (DMN) and the salience network, which are associated with the detection and integration of emotional and sensory stimuli. Research indicates that these networks contain key areas for integrating emotional and physical states, and functional connectivity impairments between these networks and other brain regions can contribute to patients' alertness, subjective distress, and poor sleep continuity.

[0272] 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 are somewhat similar to the vulnerability pattern in Alzheimer's patients.

[0273] In patients with excessive sleep, the default mode network is affected. For example, in idiopathic excessive sleep, different DMN centers (precuneus and medial prefrontal cortex) show significant changes, and functional connectivity in the DMN is associated with the severity of self-reported sleepiness.

[0274] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, involving sleep regulation and cognitive functions such as responsiveness and alertness. Furthermore, functional connectivity in the DMN differs fundamentally between early and late circadian rhythm phenotypes. Like other forms of sleep disorders, circadian rhythm disturbances lead to alterations in brain functional connectivity. Changes in resting-state brain functional connectivity have been reported in various disorders involving circadian rhythm disturbances.

[0275] Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders that represent non-REM parasomnia.

[0276] The precuneus is involved in the analysis and integration of visual, auditory, and somatosensory information, as well as the monitoring of movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnias, the default mode network is affected.

[0277] Resting-state fMRI studies of patients with sleep-related breathing disorders, such as obstructive sleep apnea (OSA), have shown that long-term exposure to oxidative stress, intermittent hypoxia, hypocapnia and hypercapnia, and sleep fragmentation are some of the major causes of OSA-related brain injury, which may lead to significant global and regional connectivity deficits, particularly in the default mode network (DMN) and areas involved in arousal and sensorimotor systems.

[0278] Sleep-related motor disorders, such as periodic limb movements during sleep, are reflected by alterations in the prefrontal motor control pathway (a subregion of the default mode network). Additionally, activity can be observed in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem.

[0279] In many cases, the resting-state networks involved in sleep regulation are also involved in social / emotional withdrawal or alienation. Therefore, according to the present invention, influencing these networks through the therapy according to the present invention will lead to an improvement in sleep disorders, and if the treated patient suffers from social / emotional withdrawal or alienation, it will also lead to an improvement in social / emotional withdrawal or alienation.

[0280] Clinical data from studies on patients with TRD or postpartum depression (PPD) have confirmed that sleep disorders can be successfully treated.

[0281] In studies involving the administration of 5-MeO-DMT, among other things, the MADRS item “reduced sleep”, which reflects insomnia, was evaluated.

[0282] The MADRS program's "reduced sleep" rating represents a decrease in sleep duration or depth compared to a participant's normal sleep pattern when they are healthy. A score of 0.2 indicates mild difficulty falling asleep, or slightly reduced, shallower, or more fragmented sleep. A score of 4 indicates a reduction or interruption of at least two hours of sleep. A score of 6 indicates less than two or three hours of sleep.

[0283] In the study group receiving the individualized dosing regimen, all eight patients had a total MADRS score of 25 for “reduced sleep” at baseline. On day 1 post-treatment, the earliest time point for assessing the treatment’s effect on sleep, the score decreased to 12, corresponding to a 13-point or 52% improvement. On day 7 post-treatment, the score decreased to 9, corresponding to a 16-point or 64% improvement.

[0284] In the 12mg group, all four patients had a total MADRS score of 12 for “reduced sleep” at baseline. On day 1 after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. On day 7 after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0285] Therefore, the score for "reduced sleep," a scale item particularly associated with sleep disorders, showed significant improvement. The inventors concluded that 5-MeO-DMT can be used to treat sleep disorders, especially in patients suffering from mental or neurological disorders.

[0286] Treatment of patients with sleep disorders (especially insomnia) and related social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvements in sleep disorders (especially insomnia).

[0287] The reduction or elimination of social / emotional withdrawal or alienation in patients with sleep disorders (especially insomnia) was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0288] The reduction or elimination of social / emotional withdrawal or alienation in patients with sleep disorders (especially insomnia) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with sleep disorders (especially insomnia) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0289] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (especially insomnia) is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0290] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (particularly insomnia) (reflected at least as an improvement in the Sneaks-Hamilton Symptom Assessment Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of cessation of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (particularly insomnia) (reflected at least as an improvement in the SHAPS score) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of cessation of the acute psychedelic experience following the last administration to the assessment time.

[0291] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (particularly insomnia) is reflected at least in the following time: approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0292] The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with sleep disorders (particularly insomnia) (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with sleep disorders (particularly insomnia) (reflected at least as an improvement in the DARS score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0293] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (particularly insomnia) is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0294] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with sleep disorders (especially insomnia) (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Anhedonia trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with sleep disorders (especially insomnia) (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0295] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with sleep disorders (particularly insomnia) is reflected at least as a mean improvement in the DSM-5 Personality Inventory (PID-5) – Adults’ withdrawal traits at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0296] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with sleep disorders (particularly insomnia) (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the end of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with sleep disorders (especially insomnia) (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0297] As stated above, social / emotional withdrawal or alienation is an important aspect of sleep disorders, particularly insomnia. Therefore, improvement in social / emotional withdrawal or alienation will also lead to improvement in sleep disorders, particularly insomnia. Since social / emotional withdrawal or alienation also affects other aspects of sleep disorders, the inventors conclude that improvement in social / emotional withdrawal or alienation will also contribute to the overall improvement of sleep disorders, particularly insomnia.

[0298] If a patient presents with idiopathic sleep disorder and also suffers from related social / emotional withdrawal or alienation, the clinical response can 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 reduction of at least 1 point. Preferably, the CGI-S score decreases by at least 2 points and / or drops to 0 points. Particularly preferably, the CGI-S score decreases by at least 3 points and / or drops to 0 points.

[0299] Improvement in idiopathic sleep disorders (reflected by a decrease in CGI-S score) in patients who also suffered from associated social / emotional withdrawal or alienation was observed on day 1, e.g., approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; day 7; day 14; and / or day 28.

[0300] Improvement in idiopathic sleep disorders in patients also suffering from related social / emotional withdrawal or alienation (reflected by a decrease in the CGI-S score in patients with related social / emotional withdrawal or alienation) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. Improvement in idiopathic sleep disorders in patients also suffering from related social / emotional withdrawal or alienation (reflected by a decrease in the CGI-S score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0301] In one implementation, improvement in idiopathic sleep disorder (reflected as a decrease in CGI-S score) in patients also suffering from associated social / emotional withdrawal or alienation is observed on day 7 of the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, and preferably continues for at least 14 days, more preferably for at least 28 days.

[0302] If a patient has idiopathic sleep disorder and also suffers from associated social / emotional withdrawal or alienation, improvement in the sleep disorder (reflected at least by a “significant improvement” score on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) scale) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0303] If a patient presents with idiopathic sleep disorder and also suffers from associated social / emotional withdrawal or alienation, improvement in the sleep disorder (reflected at least as a reduction in the “significant improvement” score on the CGI-I or PGI-I scale) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0304] Improvement in idiopathic sleep disorders in patients who also suffer from related social / emotional withdrawal or alienation can also be assessed using any other scale that reflects changes in sleep quality or quantity, as described above, such as the Pittsburgh Sleep Quality Index (PSQI).

[0305] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or below.

[0306] Improvement in idiopathic sleep disturbances (reflected by a decrease in the total PSQI score, particularly to 5 or below) in patients also suffering from associated social / emotional withdrawal or alienation preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, with the recall period from the time of cessation of the acute psychedelic experience following the last administration to the assessment time. This improvement in idiopathic sleep disturbances (reflected by a decrease in the total PSQI score) in patients also suffering from associated social / emotional withdrawal or alienation preferably continues for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, with the recall period from the time of cessation of the acute psychedelic experience following the last administration to the assessment time.

[0307] Improvement in idiopathic sleep disorders (reflected by a decrease in the total PSQI score) in patients who also suffered from associated social / emotional withdrawal or alienation was observed on day 1, e.g., approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; day 7; day 14; and / or day 28, where the recall period was from the time point of resolution of the acute psychedelic experience following the last administration to the time point of assessment.

[0308] Social / emotional withdrawal or alienation and sleep disturbances (especially insomnia) are closely associated with mental and neurological disorders. Both social / emotional withdrawal or alienation and sleep disturbances (especially insomnia) occur within mental or neurological disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD) (such as bipolar I and bipolar II), postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); and 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 the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's dementia (AD); Lewy body dementia (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0309] Social / emotional withdrawal or alienation and sleep disorders (especially insomnia) can also occur in medical conditions that lead to related mental or neurological disorders, such as traumatic brain injury or (TBI)

[0310] The treatment according to the invention will result in improvement of social / emotional withdrawal or alienation and sleep disorders (especially insomnia), as well as improvement of related mental or neurological disorders, examples of which are listed above.

[0311] Treatment of social / emotional withdrawal or alienation and mental and neurological disorders

[0312] In patients suffering from social / emotional withdrawal or alienation associated with mental or neurological disorders, treatment of social / emotional withdrawal or alienation according to the present invention leads to improvement of the disorder associated with social / emotional withdrawal or alienation.

[0313] Although social / emotional withdrawal or alienation can be considered a treatable disorder, unrelated to any other illness, disorder, or symptom an individual may have, a variety of mental and neurological disorders are associated with social / emotional withdrawal or alienation. It is noteworthy that the relationship between social / emotional withdrawal or alienation and mental disorders is bidirectional. Mental disorders not only affect a patient's emotional state with social / emotional withdrawal or alienation, but social / emotional withdrawal or alienation may also be a contributing factor to the onset, development, and prognosis of mental or neurological disorders.

[0314] In many cases, resting state networks involving social / emotional withdrawal or alienation are also involved in the disorders listed above.

[0315] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in the resting-state network. When the network reconnects, this disruption leads to a reset of pathological, malformed brain connections. New, healthy functional connections are established, and these connections have a lasting effect.

[0316] Disorders characterized by depressive episodes

[0317] Several disorders are characterized by depressive episodes.

[0318] A depressive episode is a period of time characterized by depressed mood and / or loss of interest in most activities.

[0319] For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms within the same two weeks, and the symptoms represent changes in function compared to the previous period; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

[0320] Patients with disorders characterized by depressive episodes may have a treatment-resistant form of the disorder.

[0321] Patients with disorders characterized by depressive episodes often also suffer from social / emotional withdrawal or alienation.

[0322] Social / emotional withdrawal or alienation is listed as a diagnostic criterion for disorders characterized by depressive episodes. It can be assessed as part of the MADRS or BPRS assay.

[0323] The Montgomery-Asperger's Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression.

[0324] The items are: obvious grief; reported grief; anxiety; decreased sleep; decreased appetite; difficulty concentrating; lethargy; loss of sensation; pessimistic thoughts; and suicidal thoughts, with each item rated from 0 to 6. The overall rating range is 0 to 60.

[0325] The MADRS item "sensory deprivation" represents a subjective experience of reduced interest in one's surroundings or activities that normally bring pleasure. It refers to a reduced ability to respond appropriately to one's environment or people. A rating of 0 indicates normal interest in one's surroundings and other people. A rating of 1, 2, or 3 indicates a reduced ability to enjoy normal interests; a rating of 3, 4, or 5 indicates a loss of interest in one's surroundings, feelings, or friends and acquaintances; and a rating of 6 indicates experiencing emotional numbness, an inability to feel anger, sadness, or pleasure, and a complete or even painful loss of emotional connection to family and friends.

[0326] The “Affective Withdrawal” item on the Brief Psychiatric Rating Scale (BPRS) represents deficits related to the interviewer and the interviewer-situation. The interviewer rates only the degree to which the patient’s impression of failing to engage in emotional communication with others in the interview situation is assessed.

[0327] The BPRS project's "emotional blunting" represents a lowered emotional tone and a significant lack of normal feelings or participation.

[0328] For example, the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) can be used to assess social / emotional withdrawal or alienation or aspects thereof (such as anhedonia) in adults with a disorder characterized by depressive episodes.

[0329] In patients with disorders characterized by depressive episodes, alterations in functional connectivity were observed within and / or between several brain regions associated with processing, regulation, emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal.

[0330] Treatment of patients with a disorder characterized by depressive episodes (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and resulted in improvement of the disorder characterized by depressive episodes.

[0331] The reduction or elimination of social / emotional withdrawal or alienation in patients with disorders characterized by depressive episodes was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0332] The reduction or elimination of social / emotional withdrawal or alienation in patients with disorders characterized by depressive episodes occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with disorders characterized by depressive episodes preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0333] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the MADRS item “Sensory Loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0334] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with disorders characterized by depressive episodes (reflected in an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected in an improvement in the MADRS “Sensory Loss” score) in patients with disorders characterized by depressive episodes preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0335] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0336] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with disorders characterized by depressive episodes (reflected in an improvement in the BPRS “emotional withdrawal” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected in an improvement in the BPRS “emotional withdrawal” score) in patients with disorders characterized by depressive episodes preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0337] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the BPRS item “emotional blunting” score approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0338] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with disorders characterized by depressive episodes (reflected in an improvement in the BPRS “Affective Blunting” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected in an improvement in the BPRS “Affective Blunting” score) in patients with disorders characterized by depressive episodes preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0339] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0340] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the Sneaks-Hamilton Symptom Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with disorders characterized by depressive episodes preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration.

[0341] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the Anhedonia Rating Scale (DARS) score approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0342] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with disorders characterized by depressive episodes preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0343] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0344] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Adults’ anhedonia trait) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0345] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with a disorder characterized by depressive episodes is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0346] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0347] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with a disorder characterized by depressive episodes is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for adults on the avoidance of intimacy trait at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0348] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the avoidance of intimacy trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the end of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ avoidance of intimacy traits) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0349] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with a disorder characterized by depressive episodes is reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the time point of assessment.

[0350] For patients with disorders characterized by depressive episodes, a reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation in patients with disorders characterized by depressive episodes (reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0351] As stated above, social / emotional withdrawal or alienation is closely associated with disorders characterized by depressive episodes. Therefore, improvements in social / emotional withdrawal or alienation also lead to improvements in disorders characterized by depressive episodes. Since social / emotional withdrawal or alienation also affects other aspects of disorders characterized by depressive episodes, the inventors conclude that the observed improvements in social / emotional withdrawal or alienation also contribute to overall improvements in disorders characterized by depressive episodes.

[0352] Improvement in the disorder characterized by depressive episodes (reflected by a decrease in CGI-S score) in patients who also suffered from related social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0353] Improvement in the depressive episode-characterized disorder (reflected by a decrease in CGI-S score) in patients who also suffer from related social / emotional withdrawal or alienation occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This improvement (reflected by a decrease in CGI-S score) in patients who also suffer from related social / emotional withdrawal or alienation preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0354] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects a person's feelings, thoughts, and behaviors, and can lead to a variety of emotional and physical problems.

[0355] Patients with MDD may develop a treatment-resistant form of the disorder.

[0356] The patient may have developed treatment resistance. Treatment resistance means that the patient has not achieved adequate improvement after at least two adequate courses of treatment. This is particularly true if the patient has not achieved adequate improvement after at least two adequate courses of treatment, at least one of which is pharmacological therapy; for example, the patient has not achieved adequate improvement after at least two adequate courses of medication. This is especially true if at least two previous treatment courses were administered during the current depressive episode.

[0357] As outlined in DSM-5, anhedonia is a core symptom and key feature of MDD.

[0358] Depressive symptoms are also associated with reduced social time. Social withdrawal is common and is linked to suicidal ideation in patients with MDD.

[0359] Social / emotional withdrawal or alienation in patients with MDD can be assessed as part of an MADRS or BPRS assay. Social / emotional withdrawal or alienation, or at least aspects thereof, can also be assessed, for example, using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0360] In patients with MDD, functional connectivity impairments and modulations were observed within and / or between multiple resting-state networks (including the DMN, saliency network, executive control network, and limbic network). These functional connections differed significantly from those observed in healthy controls.

[0361] Treatment of patients with MDD (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in MDD.

[0362] The patient may have moderate to severe MDD, indicated by a Montgomery-Asperger's Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or higher. Further consideration may be given for severe major depressive disorder, indicated by a Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or higher.

[0363] The reduction or elimination of social / emotional withdrawal or alienation in patients with MDD was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0364] The reduction or elimination of social / emotional withdrawal or alienation in patients with MDD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0365] The reduction or elimination of social / emotional withdrawal or alienation (especially sensory loss) in patients with MDD is reflected at least as an improvement in the MADRS item “Sensory Loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0366] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with MDD (reflected in an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with MDD (reflected in an improvement in the MADRS “Sensory Loss” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0367] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with MDD is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0368] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with MDD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with MDD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0369] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with MDD is reflected at least as an improvement in the BPRS item “emotional blunting” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0370] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with MDD (reflected in an improvement in the BPRS “Affective Bluntness” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with MDD (reflected in an improvement in the BPRS “Affective Bluntness” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0371] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0372] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with MDD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment.

[0373] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD is reflected at least in an improvement in the Anhedonia Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0374] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with MDD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0375] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0376] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Adult Anhedonia Trait) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the time point of assessment.

[0377] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with MDD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0378] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal traits in adults) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0379] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with MDD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the avoidance of intimacy trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0380] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the avoidance of intimacy trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ avoidance of intimacy traits) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0381] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with MDD is reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0382] The reduction or elimination of social / emotional withdrawal or alienation in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation in patients with MDD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time.

[0383] As stated above, social / emotional withdrawal or alienation is closely related to MDD. Therefore, improvements in social / emotional withdrawal or alienation will also lead to improvements in MDD. Since social / emotional withdrawal or alienation also affects other aspects of MDD, the inventors conclude that the observed improvements in social / emotional withdrawal or alienation will also contribute to the overall improvement of MDD.

[0384] Improvement in MDD (reflected by a decrease in CGI-S score) in patients who also suffered from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0385] Improvement in MDD (reflected by a decrease in CGI-S score) in patients who also suffer from associated social / emotional withdrawal or alienation occurred no later than approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This improvement in MDD (reflected by a decrease in CGI-S score) in patients who also suffer from associated social / emotional withdrawal or alienation preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0386] Another aspect of MDD in patients also suffering from related social / emotional withdrawal or alienation is suicidal ideation, which can be treated with the administration of 5-MeO-DMT. 5-MeO-DMT can be administered to patients with MDD also suffering from related social / emotional withdrawal or alienation to reduce or eliminate suicidal ideation.

[0387] In the aforementioned clinical studies involving patients with TRD and administration of 5-MeO-DMT, among other things, the MADRS program's "suicidal ideation" was evaluated.

[0388] “Suicidal ideation” represents a feeling that life is not worth living, a desire to die naturally, having suicidal thoughts, and / or preparing for suicide. Suicide attempts themselves should not affect the rating of this MADRS program.

[0389] A score of 0 indicates that the patient enjoys life. A score of 2 indicates that the patient is bored with life and / or has only brief suicidal thoughts. A score of 4 indicates that the patient feels better off dead, suicidal thoughts are common, and suicide is seen as a possible solution, but the patient has no specific plan or intention. A score of 6 indicates that the patient has a clear suicide plan and / or is actively preparing for it.

[0390] The MADRS scale items are particularly associated with suicidal ideation.

[0391] In the study group receiving the individualized dosing regimen, all 8 patients had a total MADRS score of 11 for suicidal ideation at baseline. Two hours later, the score decreased to 3, corresponding to an 8-point or 73% improvement. On day 1 post-treatment, the score decreased to 1, corresponding to a 10-point or 91% improvement. On day 7 post-treatment, the score decreased to 3, corresponding to an 8-point or 73% improvement.

[0392] In the 12mg group, all four patients had a total MADRS score of 8 for "suicidal thoughts" at baseline. Two hours later, the score decreased to 3, corresponding to a 5-point or 63% improvement. On day 1 post-treatment, the score decreased to 5, corresponding to a 3-point or 38% improvement. On day 7 post-treatment, the score decreased to 7, corresponding to a 1-point or 13% improvement.

[0393] Therefore, the scores for the scale item "suicidal ideation," which is particularly associated with suicidal ideation, were significantly improved, at least in patients with individualized dosing regimens. The inventors concluded that 5-MeO-DMT can be used to treat suicidal ideation in patients with MDD.

[0394] Therefore, according to the present invention, treatment for patients with MDD associated with social / emotional withdrawal or alienation can reduce or eliminate suicidal ideation.

[0395] The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or alienation is reflected at least as an improvement in the MADRS program suicidal ideation score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0396] The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or alienation (reflected at least as an improvement in the MADRS suicidal ideation score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of suicidal ideation in patients with MDD associated with social / emotional withdrawal or alienation (reflected at least as an improvement in the MADRS suicidal ideation score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0397] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), the dosing regimen described herein may be preferred for administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof to patients with MDD associated with social / emotional withdrawal or alienation without a significant risk of inducing mania or hypomania.

[0398] Preferably, patients with MDD associated with social / emotional withdrawal or alienation do not experience treatment-induced mania or hypomania.

[0399] Bipolar disorder (BD) is a mental health condition characterized by dramatic mood swings, including depressed mood (major depressive episodes) and elevated mood (manic or hypomanic episodes). BD is a relapsing chronic disorder affecting more than 1% of the global population, regardless of their racial origin or socioeconomic status.

[0400] If at least one manic episode occurs (whether or not accompanied by a depressive episode), BD is classified as bipolar I. If at least one hypomanic episode (but not a full-blown manic episode) and one major depressive episode occur, BD is classified as bipolar II. If these symptoms are caused by medication or a medical problem, they are not diagnosed as bipolar disorder.

[0401] Patients with BD (including bipolar I and bipolar II) may develop treatment-resistant forms of the disorder.

[0402] The patient may have developed treatment resistance. Treatment resistance means that the patient has not achieved adequate improvement after at least two adequate courses of treatment. This is particularly true if the patient has not achieved adequate improvement after at least two adequate courses of treatment, at least one of which is pharmacological therapy; for example, the patient has not achieved adequate improvement after at least two adequate courses of medication. This is especially true if at least two previous treatment courses were administered during the current depressive episode.

[0403] Different brain regions in patients with bipolar I and bipolar II are associated with emotional blunting and emotional withdrawal.

[0404] In a study of 197 adolescents with bipolar disorder, 90.9% of them experienced anhedonia during major depressive episodes. The severity of symptoms was significantly correlated with the severity of the disorder.

[0405] Single dose 0.5mg kg- 1 Ketamine infusion rapidly reduces anhedonia levels in patients with treatment-resistant bipolar depression. A single infusion has an onset of action within 40 minutes and lasts for up to 14 days. Subgroup positron emission tomography (PET) results from these individuals revealed that glucose metabolism in the dorsal anterior cingulate cortex (an element of the DAN) and the putamen of the brain (part of the basal ganglia RSN) enhanced the anhedonia-reducing effect.

[0406] Social / emotional withdrawal or alienation in patients with BD can be assessed as part of the MADRS, BPRS, or BDRS assays. Social / emotional withdrawal or alienation, or at least aspects thereof, can also be assessed, for example, using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Disorder of Ecstasy Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0407] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on clinical interviews, the BDRS program assesses the severity of depressive and / or mixed symptoms experienced by the patient in the current and past few days. If current symptoms are inconsistent with those of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and a maximum score of 60. Higher scores indicate greater severity.

[0408] The problems involve depressive mood; sleep disturbances; appetite disturbances; decreased social participation; decreased energy and activity; decreased motivation; impaired attention and memory; anxiety; anhedonia; emotional detachment; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; instability; increased motor drive; increased speech; and agitation.

[0409] Each aspect was evaluated and assigned a score of 0, 1, 2, or 3.

[0410] The BDRS project's "Reduced Social Engagement" report indicates reduced social and interpersonal participation or interaction. A score of 0 indicates normal participation; 1 (mild) indicates slightly reduced social engagement but no impairment in social or interpersonal function; 2 (moderate) indicates significantly reduced social engagement with some functional sequelae, such as avoidance of some social engagement or conversation; and 3 (severe) indicates significantly reduced social interaction or avoidance of almost all forms of social contact, such as the patient refusing to answer the phone or see friends or family.

[0411] The BPRS item "anhedonia" is associated with a reduced ability to subjectively experience pleasure in daily activities. A score of 0 indicates no reduction in the ability to subjectively experience pleasure in daily activities; 1 (mild) indicates a slight reduction in the ability to experience pleasure in pleasant daily activities; 2 (moderate) indicates a significant reduction in the ability to experience pleasure in pleasant daily activities, but some pleasure is still retained in isolated activities; and 3 (severe) indicates a complete inability to experience pleasure.

[0412] The BDRS item "Affective Disinterestedness" refers to the subjective feeling of a reduction in the intensity or range of sensations or feelings. A score of 0 indicates no subjective feeling of a reduction in the intensity or range of sensations or feelings; 1 (mild) indicates a slight reduction in the range of feelings or a temporary reduction in the range or intensity of sensations; 2 (moderate) indicates a significant reduction in the range or intensity of sensations but some feelings are retained, such as an inability to cry; and 3 (severe) indicates a significant and general reduction in the range of feelings or an inability to experience normal emotions.

[0413] Patients with bipolar disorder exhibit characteristic abnormalities in internal organization and the interconnectivity of resting-state networks. Resting-state functional magnetic resonance imaging (fMRI) studies, compared to healthy controls, have demonstrated altered functional connectivity in specific regions within and / or between the default mode network, salience network, and central executive network. Notably, altered functional connectivity within the default mode network has also been observed in patients with sleep disorders.

[0414] Treatment of patients with BD (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in BD.

[0415] Typically, patients with BD, whether diagnosed with bipolar II or bipolar I, will experience a current major depressive episode.

[0416] The severity of a current major depressive episode can be assessed using the Montgomery-Asperger Depression Rating Scale (MADRS). Patients may have a total score of 19 or higher, such as 24 or higher, and especially 37 or higher.

[0417] Alternatively, the patient may have a total score of 19 on the Bipolar Depression Rating Scale (BDRS), such as 24 or greater, especially 37 or greater.

[0418] The reduction or elimination of social / emotional withdrawal or alienation in patients with bipolar disorder was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0419] The reduction or elimination of social / emotional withdrawal or alienation in patients with BD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with BD preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0420] The reduction or elimination of social / emotional withdrawal or alienation (especially sensory loss) in patients with BD is reflected at least as an improvement in the MADRS item “Sensory Loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0421] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with BD (reflected in an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with BD (reflected in an improvement in the MADRS “Sensory Loss” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0422] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with BD is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0423] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with BD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with BD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0424] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with BD is reflected at least as an improvement in the BPRS item “emotional blunting” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0425] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with BD (reflected in an improvement in the BPRS “Affective Bluntness” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with BD (reflected in an improvement in the BPRS “Affective Bluntness” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0426] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly reduced social engagement) in patients with BD is reflected at least as an improvement in the BDRS item “Reduced Social Engagement” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0427] The reduction or elimination of social / emotional withdrawal or alienation (particularly reduced social participation) in patients with BD (reflected in an improvement in the BDRS score for "Reduced Social Participation") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. This reduction or elimination of social / emotional withdrawal or alienation (particularly reduced social participation) in patients with BD (reflected in an improvement in the BDRS score for "Reduced Social Participation") preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0428] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD is reflected at least as an improvement in the BDRS item “anhedonia” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0429] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD (reflected in an improvement in the BDRS "anhedonia" score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD (reflected in an improvement in the BDRS "anhedonia" score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0430] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional apathy) in patients with BD is reflected at least as an improvement in the BDRS item “emotional apathy” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0431] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional coldness) in patients with BD (reflected in an improvement in the BDRS “emotional coldness” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional coldness) in patients with BD (reflected in an improvement in the BDRS “emotional coldness” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0432] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0433] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with BD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment.

[0434] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD is reflected at least in an improvement in the Dimensional Anhedonia Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0435] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with BD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0436] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the time point of assessment.

[0437] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Anhedonia Trait in Adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0438] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with BD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0439] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0440] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with BD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the avoidance of intimacy trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0441] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the avoidance of intimacy trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ avoidance of intimacy traits) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0442] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with BD is reflected at least as an improvement in the mean score of the Domain Alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0443] The reduction or elimination of social / emotional withdrawal or alienation in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation in patients with BD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time.

[0444] As stated above, social / emotional withdrawal or alienation is closely related to BD. Therefore, improvements in social / emotional withdrawal or alienation will also lead to improvements in BD. Since social / emotional withdrawal or alienation also affects other aspects of BD, the inventors conclude that observed improvements in social / emotional withdrawal or alienation will also contribute to overall improvements in BD.

[0445] Improvement in BD (reflected by a decrease in CGI-S score) in patients who also suffer from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0446] Improvement in BD (reflected by a decrease in CGI-S score) in patients with associated social / emotional withdrawal or alienation occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. Furthermore, improvement in bipolar disorder (reflected by a decrease in CGI-S score) in patients with associated social / emotional withdrawal or alienation preferably persisted for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0447] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT or its pharmaceutically acceptable salts may be preferred for patients with bipolar disorder (such as bipolar I and bipolar II) associated with social / emotional withdrawal or alienation, without a significant risk of inducing mania or hypomania.

[0448] Preferably, patients with bipolar disorder associated with social / emotional withdrawal or alienation (such as bipolar I and bipolar II) do not experience treatment-induced mania or hypomania.

[0449] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks after childbirth. More than 50% of women may experience a brief period of low mood or tearfulness after delivery, but a small percentage may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0450] Patients with PPD may develop a treatment-resistant form of the disorder.

[0451] A data analysis of 663 women suffering from perinatal depression found that anhedonia and anxiety were the most prominent symptoms eight weeks postpartum.

[0452] Social isolation is one of five established dimensions associated with and predicting maternal depressive symptoms.

[0453] Perinatal major depressive disorder (PDD) is also known as perinatal major depressive disorder. According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when symptoms of major depressive disorder (MDD) appear during pregnancy or within four weeks postpartum. Therefore, individuals with PPD also experience social / emotional withdrawal or alienation, particularly anhedonia.

[0454] Social / emotional withdrawal or alienation in patients with PPD can be assessed as part of an MADRS or BPRS assay. Social / emotional withdrawal or alienation, or at least aspects thereof, can also be assessed, for example, using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Dissatisfaction Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0455] Significant changes in neural activity can be observed in brain regions important for self-regulation, empathy, emotion, and cognition in patients with PPD. PPD is associated with impaired functional connectivity within and / or between resting-state networks, such as the default mode network and the frontoparietal network.

[0456] Treatment of patients with PPD (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in PPD.

[0457] Patients may have moderate to severe PPD, indicated by a Montgomery-Asperger's Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher. Severe PPD is further considered, indicated by a Montgomery-Asperger's Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or higher.

[0458] Patients treated according to the present invention may have a Montgomery-Asperger's Depression Rating Scale (MADRS) score of 20 or higher or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

[0459] Furthermore, patients treated according to the present invention may have a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0460] Furthermore, patients treated according to the present invention may have a MADRS score of 35 or higher or a HAM-D score of 25 or higher.

[0461] The reduction or elimination of social / emotional withdrawal or alienation in patients with PPD was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0462] The reduction or elimination of social / emotional withdrawal or alienation in patients with PPD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation in patients with PPD preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0463] The reduction or elimination of social / emotional withdrawal or alienation (especially sensory loss) in patients with PPD is reflected at least as an improvement in the MADRS item “Sensory Loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0464] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with PPD (reflected in an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with PPD (reflected in an improvement in the MADRS “Sensory Loss” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0465] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with PPD is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0466] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with PPD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with PPD (reflected in an improvement in the BPRS “Emotional Withdrawal” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0467] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with PPD is reflected at least as an improvement in the BPRS item “emotional blunting” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0468] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with PPD (reflected in an improvement in the BPRS “Affective Bluntness” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with PPD (reflected in an improvement in the BPRS “Affective Bluntness” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; and more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0469] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0470] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD (reflected at least as an improvement in the Sneaks-Hamilton Symptom Assessment Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with PPD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment.

[0471] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD is reflected at least as an improvement in the Dysfunction Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0472] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with PPD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0473] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0474] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Adult Anhedonia Trait) occurred no later than approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0475] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with PPD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0476] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0477] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with PPD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the avoidance of intimacy trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0478] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the avoidance of intimacy trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ Avoidance of Intimacy Trait) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0479] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with PPD is reflected at least as an improvement in the mean score of the Domain Alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0480] The reduction or elimination of social / emotional withdrawal or alienation in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation in patients with PPD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time.

[0481] As stated above, social / emotional withdrawal or alienation is closely related to PPD. Therefore, improvements in social / emotional withdrawal or alienation also lead to improvements in PPD. Since social / emotional withdrawal or alienation also affects other aspects of PPD, the inventors conclude that observed improvements in social / emotional withdrawal or alienation also contribute to overall improvements in PPD.

[0482] Improvement in PPD (reflected by a decrease in CGI-S score) in patients who also suffer from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0483] For patients who also suffer from associated social / emotional withdrawal or alienation, improvement in PPD (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This improvement in PPD (reflected by a decrease in CGI-S score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0484] In addition, social / emotional withdrawal or alienation can impair maternal function.

[0485] For example, the Barkin Index of Maternal Function (BIMF) can be used to assess maternal function. This index is designed to measure function within one year postpartum. The BIMF is a 20-item self-reported measure of function. Each item is rated from 0 to 6, resulting in a maximum total score of 120. Higher scores indicate better maternal function.

[0486] The BIMF identifies the key functional areas of mothers during the postpartum period as: self-care, infant care, mother-child interaction, maternal mental health, social support, management, and adjustment.

[0487] A BIMF score of 95 or below is considered to represent mild maternal function impairment in this paper, a score of 80 or below is considered to represent maternal function impairment in this paper, and a score of 65 or below is considered to represent severe maternal function impairment in this paper.

[0488] The inventors have determined that increased scores on the MADRS item “sensory loss” and / or the BPRS items “emotional withdrawal” and “emotional blunting” have a negative impact on maternal function (maternal abilities related to interaction with the baby and maternal self-care).

[0489] Increased scores for sensory loss in the MADRS and / or emotional withdrawal and / or emotional blunting in the BPRS impair mental health, social support, and management. Conversely, improvements in MADRS “sensory loss” and / or BPRS “emotional withdrawal” and “emotional blunting” lead to improvements in maternal function, particularly in the BIMF functional domains of mental health, social support, and / or management.

[0490] The inventors concluded that 5-MeO-DMT can be used to treat patients with PPD to improve social / emotional withdrawal or alienation, particularly to reduce or eliminate sensory loss, emotional withdrawal and / or emotional blunting.

[0491] The inventors also concluded that reducing or eliminating sensory loss, emotional withdrawal, and / or emotional blunting by treating patients with PPD not only leads to a decrease in the total MADRS or BPRS score, but also to an improvement in maternal function, reflected in an increase in the BIMF score.

[0492] A 10% or greater improvement in the BIMF total score is preferred, with an ideal improvement of 20% or more.

[0493] Improvement in maternal function in patients with PPD was reflected at least in an improved total BIMF score on day 7, day 14, and / or day 28 following the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0494] Improvement in maternal function (reflected at least in total BIMF score) in patients with PPD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. Improvement in maternal function (reflected at least in total BIMF score) preferably continues for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0495] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), the dosing regimen described herein may be preferred for administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof to patients with PPD associated with social / emotional withdrawal or alienation without a significant risk of inducing mania or hypomania.

[0496] Preferably, patients with PPD associated with social / emotional withdrawal or alienation do not experience treatment-induced mania or hypomania.

[0497] Seasonal affective disorder (SAD) is a mood disorder with a seasonal pattern; symptoms typically begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0498] Patients with seasonal affective disorder may develop a treatment-resistant form of the disorder.

[0499] Seasonal affective disorder (SAD) is associated with social / emotional withdrawal or alienation (including social withdrawal and anhedonia). According to DSM-V, SAD is characterized by a depressive episode that meets the criteria for a major depressive episode (including anhedonia).

[0500] Social / emotional withdrawal or alienation in patients with seasonal affective disorder can be assessed as part of a MADRS or BPRS assay. Social / emotional withdrawal or alienation, or at least aspects thereof, can also be assessed, for example, using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0501] Compared with healthy controls, resting-state activities involving sensorimotor, attention, and visual processing were altered in patients with seasonal affective disorder.

[0502] In patients with seasonal affective disorder (SAD), altered functional connectivity was observed within and / or between several brain regions associated with processing, regulation, emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Impaired functional connectivity was observed within and / or between the DMN, salience network, executive control network, and limbic network. This functional connectivity differed significantly from that observed in healthy controls.

[0503] Treatment of patients with seasonal affective disorder (SAD) (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in SAD.

[0504] The reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0505] The reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0506] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with seasonal affective disorder is reflected at least as an improvement in the MADRS item “sensory loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0507] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with seasonal affective disorder (SAD) (reflected as an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with SAD (reflected as an improvement in the MADRS “Sensory Loss” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0508] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with seasonal affective disorder is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28.

[0509] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with seasonal affective disorder (SAD) (reflected by an improvement in the BPRS "Emotional Withdrawal" score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with SAD (reflected by an improvement in the BPRS "Emotional Withdrawal" score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0510] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with seasonal affective disorder is reflected at least as an improvement in the BPRS item “emotional blunting” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0511] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with seasonal affective disorder (SAD) (reflected in an improvement in the BPRS “Affective Blunting” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with SAD (reflected in an improvement in the BPRS “Affective Blunting” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0512] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0513] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder (SAD) (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with SAD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment.

[0514] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder is reflected at least in an improvement in the Anhedonia Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0515] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder (SAD) (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with SAD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0516] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0517] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Anhedonia Trait in Adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the end of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Anhedonia Trait in Adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time.

[0518] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with seasonal affective disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0519] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the end of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0520] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with seasonal affective disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for adults on the avoidance of intimacy trait at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0521] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the avoidance of intimacy trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the end of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ avoidance of intimacy traits) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0522] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder is reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0523] The reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation in patients with seasonal affective disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of resolution of the acute psychedelic experience following the last administration to the assessment time.

[0524] As stated above, social / emotional withdrawal or alienation is closely associated with seasonal affective disorder (SAD). Therefore, improvements in social / emotional withdrawal or alienation also lead to improvements in SAD. Since social / emotional withdrawal or alienation also affects other aspects of SAD, the inventors conclude that the observed improvements in social / emotional withdrawal or alienation also contribute to the overall improvement of SAD.

[0525] Improvement in seasonal affective disorder (reflected by a decrease in CGI-S score) in patients who also suffered from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0526] Improvement in seasonal affective disorder (SAD) in patients also suffering from associated social / emotional withdrawal or alienation (reflected by a decrease in CGI-S score) occurred no later than approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This improvement in SAD (reflected by a decrease in CGI-S score) in patients also suffering from associated social / emotional withdrawal or alienation preferably persisted for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0527] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT or its pharmaceutically acceptable salts may be preferably administered to patients with seasonal affective disorder associated with social / emotional withdrawal or alienation using the dosing regimen described herein, without a significant risk of inducing mania or hypomania.

[0528] Preferably, patients with seasonal affective disorder associated with social / emotional withdrawal or alienation do not experience treatment-induced mania or hypomania.

[0529] Persistent depressive disorder

[0530] Persistent depressive disorder, also known as dysphoric mood, is a chronic form of depression. A diagnosis of persistent depressive disorder is made if depression is present for most of the day, most of the day, for at least two years. Any asymptomatic periods are less than two months.

[0531] To be depressed, you must have two or more of the following symptoms: 1. hopelessness; 2. lack of energy or fatigue; 3. low self-esteem; 4. decreased sleep (insomnia) or increased sleep (excessive sleep); 5. loss of appetite or overeating; 6. difficulty making decisions or difficulty concentrating.

[0532] Patients with persistent depressive disorder may develop a treatment-resistant form of the disorder.

[0533] According to DSM-V, persistent depressive disorder is characterized by the criteria for major depressive disorder and may persist for up to 2 years. Major depressive disorder includes anhedonia. Social withdrawal is also a common symptom in patients with persistent depressive disorder.

[0534] Social / emotional withdrawal or alienation in patients with persistent depressive disorder can be assessed as part of an MADRS or BPRS assessment. Social / emotional withdrawal or alienation, or at least aspects thereof, can also be assessed, for example, using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Anhedonia Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0535] In patients with persistent depressive disorder, altered functional connectivity was observed within and / or between several brain regions associated with processing, regulation, emotional memory, rumination-related cognitive processes, impaired concentration, and physiological arousal. Impaired functional connectivity was observed within and / or between the DMN, salience network, executive control network, and limbic network. This functional connectivity differed significantly from that observed in healthy controls.

[0536] In patients with persistent depressive disorder, impairment and modulation of functional connectivity among multiple resting-state networks (including the DMN, salience network, executive control network, and limbic network) were observed. This functional connectivity differed significantly from that observed in healthy controls.

[0537] Treatment of patients with persistent depressive disorder (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and resulted in improvement of persistent depressive disorder.

[0538] The reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0539] The reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0540] The reduction or elimination of social / emotional withdrawal or alienation (especially sensory loss) in patients with persistent depressive disorder is reflected at least as an improvement in the MADRS item “sensory loss” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0541] The reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with persistent depressive disorder (reflected in an improvement in the MADRS “Sensory Loss” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. This reduction or elimination of social / emotional withdrawal or alienation (particularly sensory loss) in patients with persistent depressive disorder (reflected in an improvement in the MADRS “Sensory Loss” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0542] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with persistent depressive disorder is reflected at least as an improvement in the BPRS item “emotional withdrawal” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0543] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with persistent depressive disorder (reflected in an improvement in the BPRS “Emotional Withdrawal” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with persistent depressive disorder (reflected in an improvement in the BPRS “Emotional Withdrawal” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0544] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with persistent depressive disorder is reflected at least as an improvement in the BPRS item “emotional blunting” score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0545] The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with persistent depressive disorder (reflected in an improvement in the BPRS “Affective Blunting” score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof. The reduction or elimination of social / emotional withdrawal or alienation (particularly emotional blunting) in patients with persistent depressive disorder (reflected in an improvement in the BPRS “Affective Blunting” score) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof.

[0546] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with persistent depressive disorder is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0547] For patients with persistent depressive disorder, the reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with persistent depressive disorder preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration.

[0548] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with persistent depressive disorder is reflected at least in an improvement in the Anhedonia Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28.

[0549] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with persistent depressive disorder (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with persistent depressive disorder preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0550] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with persistent depressive disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0551] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Adults’ anhedonia trait) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0552] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with persistent depressive disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0553] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0554] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly emotional withdrawal) in patients with persistent depressive disorder is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for adults on the avoidance of intimacy trait at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0555] The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Adults’ avoidance of intimacy traits) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially emotional withdrawal) in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Adults’ avoidance of intimacy traits) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0556] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder is reflected at least as an improvement in the mean score of the domain alienation trait on the DSM-5 Personality Inventory (PID-5) for adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0557] The reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the assessment time point. The reduction or elimination of social / emotional withdrawal or alienation in patients with persistent depressive disorder (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - Domain Alienation trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the assessment time point.

[0558] As stated above, social / emotional withdrawal or alienation is closely associated with persistent depressive disorder. Therefore, improvements in social / emotional withdrawal or alienation also lead to improvements in persistent depressive disorder. Since social / emotional withdrawal or alienation also affects other aspects of persistent depressive disorder, the inventors conclude that the observed improvements in social / emotional withdrawal or alienation also contribute to the overall improvement of persistent depressive disorder.

[0559] Improvement in persistent depressive disorder (reflected by a decrease in CGI-S score) in patients also suffering from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0560] Improvement in persistent depressive disorder (reflected by a decrease in CGI-S score) in patients also suffering from associated social / emotional withdrawal or alienation occurred no later than approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. This improvement in persistent depressive disorder (reflected by a decrease in CGI-S score) in patients also suffering from associated social / emotional withdrawal or alienation preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0561] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT or its pharmaceutically acceptable salts may be preferably administered to patients with persistent depressive disorders associated with social / emotional withdrawal or alienation using the dosing regimen described herein, without a significant risk of inducing mania or hypomania.

[0562] Preferably, patients with persistent depressive disorder associated with social / emotional withdrawal or alienation do not experience treatment-induced mania or hypomania.

[0563] Anxiety disorder

[0564] Anxiety disorder is a mental health condition. Symptoms include feelings of tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety is associated with fear and manifests as a future-oriented emotional state, consisting of a complex cognitive, emotional, physiological, and behavioral response system related to preparing for anticipated events or situations perceived as threatening.

[0565] Patients with anxiety disorders may develop treatment-resistant forms of the disorder.

[0566] Social / emotional withdrawal or alienation, or at least one aspect thereof, can be assessed, for example, by using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Dissatisfaction Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0567] Anxiety disorders are associated with altered functional connectivity of resting-state networks. Anxiety disorders manifest as abnormalities in the default mode network (DMN), which influences self-awareness; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. The resting-state balance within and / or between each of these networks (e.g., the SMN and SN) relative to the DMN may be abnormal in different anxiety disorders.

[0568] Treatment of patients with anxiety disorders (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in the anxiety disorder.

[0569] The reduction or elimination of social / emotional withdrawal or alienation in patients with anxiety disorders was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0570] The reduction or elimination of social / emotional withdrawal or alienation in patients with anxiety disorders occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with anxiety disorders preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0571] The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with anxiety disorders is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at the following times: approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0572] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with anxiety disorders (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of cessation of the acute psychedelic experience following the last administration to the assessment time. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with anxiety disorders preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time from the time of cessation of the acute psychedelic experience following the last administration to the assessment time.

[0573] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with anxiety disorders is reflected at least in an improvement in the Anhedonia Dimensional Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0574] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with anxiety disorders (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with anxiety disorders preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0575] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with anxiety disorders is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for the anhedonia trait in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0576] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with anxiety disorders (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – Anhedonia Trait in Adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with anxiety disorders (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0577] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with anxiety disorders is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0578] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with anxiety disorders (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with anxiety disorders (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; particularly for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable saline thereof, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0579] As stated above, social / emotional withdrawal or alienation occurs in patients with anxiety disorders. Therefore, improvement in social / emotional withdrawal or alienation also leads to improvement in anxiety disorders. Since social / emotional withdrawal or alienation also affects other aspects of anxiety disorders, the inventors conclude that the observed improvement in social / emotional withdrawal or alienation also contributes to the overall improvement of anxiety disorders.

[0580] Improvement in anxiety disorders (reflected by a decrease in CGI-S score) in patients who also suffered from associated social / emotional withdrawal or alienation was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0581] Improvement in anxiety disorders (reflected by a decrease in CGI-S score) in patients also suffering from related social / emotional withdrawal or alienation occurred no later than approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. This improvement in anxiety disorders (reflected by a decrease in CGI-S score) in patients also suffering from related social / emotional withdrawal or alienation preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0582] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and uncontrollable worry about a wide range of situations and problems. People with GAD may anticipate disasters and may worry excessively about money, health, family, work, or other issues.

[0583] An individual is diagnosed with generalized anxiety disorder (GAD) when they experience persistent anxiety about everyday challenges, and this anxiety is disproportionate to the perceived threat. Individuals with GAD typically experience excessive fear that lasts for months to years.

[0584] GAD can interfere with social, professional, or other important functional areas.

[0585] Patients with GAD may develop a treatment-resistant form of the disorder.

[0586] A study of 224 individuals primarily diagnosed with GAD found that anhedonia was a key factor in the association between quality of life (QoL), sleep problems, and negative cognition.

[0587] A large-scale longitudinal study of older adults found that social isolation was associated with higher anxiety and depressive symptoms.

[0588] Social / emotional withdrawal or alienation, or at least one aspect thereof, can be assessed, for example, by using the Sneaks-Hamilton Pleasure Scale (SHAPS), the Dimensional Dissatisfaction Rating Scale (DARS), or the DSM-5 Personality Inventory (PID-5) for adults.

[0589] Patients with GAD exhibit altered functional connectivity, particularly within the default mode network.

[0590] Treatment of patients with GAD (including treatment-resistant forms of the disorder) and associated social / emotional withdrawal or alienation with 5-MeO-DMT or its pharmaceutically acceptable salts reduced or eliminated social / emotional withdrawal or alienation and led to improvement in GAD.

[0591] The reduction or elimination of social / emotional withdrawal or alienation in patients with GAD was observed approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0592] The reduction or elimination of social / emotional withdrawal or alienation in patients with GAD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt. The reduction or elimination of social / emotional withdrawal or alienation in patients with GAD preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt.

[0593] The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with GAD is reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0594] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with GAD (reflected at least as an improvement in the Sneaks-Hamilton Pleasure Scale (SHAPS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the SHAPS score) in patients with GAD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the onset of the recall period is no earlier than the time between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment.

[0595] Alternatively, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with GAD is reflected at least in an improvement in the Anhedonia Rating Scale (DARS) score at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1, for example, approximately 24 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 7; on day 14; and / or on day 28.

[0596] The reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with GAD (reflected at least as an improvement in the Dimensional Anhedonia Rating Scale (DARS) score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline. The reduction or elimination of social / emotional withdrawal or alienation (reflected at least as an improvement in the DARS score) in patients with GAD preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline.

[0597] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly anhedonia) in patients with GAD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for anhedonia traits in adults at least 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, about 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the time point of assessment.

[0598] The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with GAD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) occurred no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period was no earlier than the time point between the time of resolution of the acute psychedelic experience following the last administration and the time of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially anhedonia) in patients with GAD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - anhedonia trait in adults) preferably persists for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0599] Or, or otherwise, a reduction or elimination of social / emotional withdrawal or alienation (particularly social withdrawal) in patients with GAD is reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) for withdrawal traits in adults at least approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt; on day 1 after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, for example, approximately 24 hours later; on day 7; on day 14; and / or on day 28, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience following the last administration to the assessment time point.

[0600] The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with GAD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) – the withdrawal trait in adults) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, wherein the onset of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the time point of assessment. The reduction or elimination of social / emotional withdrawal or alienation (especially social withdrawal) in patients with GAD (reflected at least as an improvement in the mean score of the DSM-5 Personality Inventory (PID-5) - withdrawal trait in adults) preferably continues for at least 6 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; particularly for at least 14 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline; more preferably for at least 28 days after the last administration of 5-MeO-DMT or its pharmaceutically acceptable saline, wherein the start of the recall period is no earlier than the time point from the time of resolution of the acute psychedelic experience after the last administration to the assessm...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from social / emotional withdrawal or alienation, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein said treatment reduces or eliminates social / emotional withdrawal or alienation.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 2, wherein the treatment reduces or eliminates anhedonia, emotional withdrawal, emotional apathy and / or decreased social engagement.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 2 or 3, wherein said reduction or elimination of social / emotional withdrawal or alienation is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 2 or 3, wherein said reduction or elimination of social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein said reduction or elimination of social / emotional withdrawal or alienation lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from a psychiatric or neurological disorder associated with the social / emotional withdrawal or alienation.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 6, wherein the patient suffering from a psychiatric or nervous system disorder suffers from a treatment-resistant form of the disorder.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from a disorder characterized by depressive episodes associated with the social / emotional withdrawal or alienation.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 8, wherein the patient suffering from a disorder characterized by a depressive episode suffers from a treatment-resistant form of the disorder.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from major depressive disorder (MDD) associated with the social / emotional withdrawal or alienation.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 10, wherein the patient suffering from MDD suffers from a treatment-resistant form of the disorder.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 10 to 11, wherein said treatment of a patient suffering from MDD associated with social / emotional withdrawal or alienation reduces or eliminates suicidal ideation.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from postpartum depression (PPD) associated with said social / emotional withdrawal or alienation.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 13, wherein the patient suffering from PPD suffers from a treatment-resistant form of the disorder.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 13 or 14, wherein the patient also suffers from impaired maternal function.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 15, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 80 or less, such as 65 or less.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 15 or 16, wherein said treatment improves maternal function.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 17, wherein said improvement in maternal function is reflected in an improvement in the BIMF total score of 10% or more, preferably 20% or more.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 17 or 18, wherein the improvement in maternal function is reflected in at least an improvement in the BIMF total score at day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 17 or 18, wherein said improvement in maternal function occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected at least in an improvement in the BIMF total score, and wherein said improvement in maternal function persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected at least in an improvement in the BIMF total score.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from bipolar disorder associated with the social / emotional withdrawal or alienation.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 21, wherein the patient suffers from bipolar disorder type II associated with the social / emotional withdrawal or alienation.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 21, wherein the patient suffers from bipolar disorder type I associated with the social / emotional withdrawal or alienation.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 21 to 23, wherein the patient suffers from a current major depressive episode.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 21 to 24, wherein the patient suffering from bipolar disorder suffers from a treatment-resistant form of the disorder.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from seasonal affective disorder associated with the social / emotional withdrawal or alienation.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 26, wherein the patient suffering from seasonal affective disorder suffers from a treatment-resistant form of the disorder.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from persistent depressive disorder associated with the social / emotional withdrawal or alienation.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 28, wherein the patient suffering from persistent depressive disorder suffers from a treatment-resistant form of the disorder.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from an anxiety disorder associated with the social / emotional withdrawal or alienation.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 30, wherein the patient suffering from an anxiety disorder suffers from a treatment-resistant form of the disorder.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from generalized anxiety disorder (GAD) associated with the social / emotional withdrawal or alienation.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 32, wherein the patient suffering from GAD suffers from a treatment-resistant form of the disorder.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from social anxiety disorder (SAD) associated with said social / emotional withdrawal or alienation.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 34, wherein the patient suffering from SAD suffers from a treatment-resistant form of the disorder.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from obsessive compulsive disorder or a related disorder associated with the social / emotional withdrawal or alienation.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 36, wherein the obsessive compulsive disorder or related disorder is obsessive compulsive disorder (OCD).

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 36 or 37, wherein the patient suffers from a treatment-resistant form of the disorder.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from body dysmorphic disorder (BDD) associated with the social / emotional withdrawal or alienation.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 39, wherein the patient suffering from BDD suffers from a treatment-resistant form of the disorder.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from post-traumatic stress disorder (PTSD) associated with the social / emotional withdrawal or alienation.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 41, wherein the patient suffering from PTSD suffers from a treatment-resistant form of the disorder.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from a pain disorder associated with the social / emotional withdrawal or alienation.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 43, wherein the patient suffers from chronic pain associated with the social / emotional withdrawal or alienation.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 43 or 44, wherein the patient suffers from a treatment-resistant form of the disorder.

46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from fibromyalgia associated with said social / emotional withdrawal or alienation.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from psychiatric and behavioral disorders due to the use of psychoactive substances associated with the social / emotional withdrawal or alienation.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 47, wherein the patient suffers from a substance use disorder (SUD) associated with the social / emotional withdrawal or alienation.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 47 or 48, wherein the patient suffers from a treatment-resistant form of the disorder.

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from a psychotic disorder associated with the social / emotional withdrawal or alienation.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 50, wherein the patient suffering from a psychotic disorder suffers from a treatment-resistant form of the disorder.

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from schizophrenia associated with said social / emotional withdrawal or alienation.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 52, wherein the patient suffering from schizophrenia suffers from a treatment-resistant form of the disorder.

54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from dementia associated with the social / emotional withdrawal or alienation.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from Alzheimer's disease dementia associated with the social / emotional withdrawal or alienation.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from dementia with Lewy bodies associated with said social / emotional withdrawal or alienation.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from vascular dementia associated with the social / emotional withdrawal or alienation.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from frontotemporal dementia associated with the social / emotional withdrawal or alienation.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from Parkinson's disease associated with the social / emotional withdrawal or alienation.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from an eating disorder associated with the social / emotional withdrawal or alienation.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 60, wherein the patient suffering from an eating disorder suffers from a treatment-resistant form of the disorder.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from autism spectrum disorder (ASD) associated with the social / emotional withdrawal or alienation.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from attention deficit hyperactivity disorder (ADHD) associated with the social / emotional withdrawal or alienation.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 63, wherein the patient suffering from ADHD suffers from a treatment-resistant form of the disorder.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from a personality disorder associated with the social / emotional withdrawal or alienation.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 65, wherein the patient suffers from schizotypal personality disorder associated with the social / emotional withdrawal or alienation.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 65 or 66, wherein the patient suffers from a treatment-resistant form of the disorder.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from borderline personality disorder (BPD) associated with said social / emotional withdrawal or alienation.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 68, wherein the patient suffering from BPD suffers from a treatment-resistant form of the disorder.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 5, wherein the social / emotional withdrawal or alienation is due to traumatic brain injury.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 6 to 70, wherein said treatment results in improvement of said diagnosed disorder in a patient who also suffers from associated social / emotional withdrawal or alienation.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 71, wherein said improvement in said diagnosed disorder in a patient who also suffers from associated social / emotional withdrawal or alienation is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 71, wherein said improvement in said diagnosed disorder in a patient who also suffers from associated social / emotional withdrawal or alienation occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, and wherein said improvement in said diagnosed disorder in a patient who also suffers from associated social / emotional withdrawal or alienation persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from sleep disturbance associated with the social / emotional withdrawal or alienation.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 74, wherein the sleep disorder is insomnia.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 74 or 75, wherein the patient suffers from idiopathic sleep disorder associated with the social / emotional withdrawal or alienation.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 74 to 76, wherein the patient suffers from a treatment-resistant form of the disorder.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 74, 75 or 77, wherein the sleep disturbance occurs in a patient suffering from associated social / emotional withdrawal or alienation and also suffering from a psychiatric or neurological disorder such as a disorder characterized by depressive episodes, or a medical health condition such as traumatic brain injury (TBI) that results in an associated psychiatric or neurological disorder, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders such as generalized anxiety disorder (GAD) and social anxiety disorder (LSID); These disorders include: post-traumatic stress disorder (PTSD); mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (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).

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 78, wherein said treatment results in improvement of social / emotional withdrawal or alienation and sleep disturbances, and further results in improvement of said associated psychiatric or said neurological disorder, or results in improvement of said medical health condition of an associated psychiatric or neurological disorder.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 74 to 79, wherein said treatment results in an improvement in said sleep disorder.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 80, wherein the improvement in sleep disturbance is observed on day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28, and the improvement is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 80, wherein said improvement in said sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, and wherein said improvement in said sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 80, wherein said improvement in said sleep disturbance is observed at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, and preferably persists until at least 14 days, more preferably until at least 28 days.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 83, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 84, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 84, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 84, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 85, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 85 or 88, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 89, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 85 or 88, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 91, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 88 to 92, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 84 to 93, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 94, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 95, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

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