5-MEO-DMT for use in treating sleep disorders

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat patients suffering from sleep disorders, and 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous routes.

Description

[Technical Field]

[0001] The present invention relates to sleep disorders, particularly psychiatric or nervous system disorders, for example disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), including bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorder; 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, fibromyalgia, and migraine; The present invention relates to improved methods for treating sleep disorders in patients suffering from mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia, dementia with Lewy bodies, vascular dementia, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; psychiatric or nervous system disorders associated with HIV, traumatic brain injury, or the post-COVID state.

[0002] The treatment involves administering to a patient in need of treatment a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] A sleep disorder (sleep dysregulation) refers to a condition that affects the quality, timing, or duration of sleep. Sleep disorders affect a person's ability to function properly while awake.

[0004] Sleep disorders may be idiopathic or may occur in association with a medical condition such as a psychiatric or nervous system disorder, and indeed several psychiatric and nervous system disorders are known to be associated with sleep disorders.

[0005] Sleep disorders can not only seriously affect quality of life, but can also lead to a variety of secondary health problems.

[0006] Thus, there is a need for treatment of sleep disorders, particularly those associated with psychiatric or nervous system disorders. Summary of the Invention

[0007] It is an object of the present invention to provide, inter alia, therapies that are more effective than previously described therapies (i.e., a) a greater percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a more rapid onset of clinical response, and / or d) a more durable clinical response).

[0008] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies that have a superior safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapies that are associated with higher patient compliance (including higher treatment initiation rates) than previously described therapies. A still further object of the present invention is to identify specific disease states and specific disease subgroups that would benefit from such improved psychoactive therapies.

[0009] The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from a sleep disorder, particularly insomnia, hypersomnia and / or a circadian rhythm disorder.

[0010] The present invention also relates to 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a sleep disorder, such as a parasomnia, a sleep-related breathing disorder, or a sleep-related movement disorder.

[0011] Sleep disorders may be idiopathic or may be psychiatric or neurological disorders, for example, disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorders; 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, fibromyalgia, and rheumatoid arthritis. It may also occur in patients suffering from myalgia, and migraine; mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; psychiatric or nervous system disorders associated with HIV, traumatic brain injury, or the post-COVID state.

[0012] The present invention also provides dose ranges and administration regimens useful for treating sleep disorders.

[0013] In the context of the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous administration.

[0014] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a hallucinogenic high. A dose of about 1 mg to about 10 mg of 5-MeO-DMT, or an equimolar amount of a pharmaceutically acceptable salt thereof, may be administered. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming an equimolar amount is used.

[0016] As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed by a licensed professional, in accordance with accepted medical practice, as suffering from a sleep disorder, or who has been diagnosed by a licensed professional, in accordance with accepted medical practice, as having a psychiatric or nervous system disorder associated with a sleep disorder, in which case evaluation of the sleep disorder may or may not be part of the diagnosis.

[0017] Diagnosis of mental or nervous system disorders may be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. As will become apparent from the discussion of specific conditions below, in some cases, the criteria may be modified or supplemented to better define patients or patient groups that would particularly benefit from the treatments of the present invention. In any case, diagnosis is by a physician or psychologist. It is not sufficient for the human subject to consider themselves to be suffering from a disorder.

[0018] As used in the context of the present invention, unless otherwise indicated, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of compounds and practice of methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0019] "Treatment of sleep disorders" is intended to include the management and care of a patient for the purpose of addressing a sleep disorder, and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of, or eliminate, a sleep disorder, which may be idiopathic or associated with a psychiatric or nervous system disorder.

[0020] Patient may suffer from treatment-resistant disease.Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy; for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses.At least two previous treatment courses are particularly carried out in the current episode of disease, for example, if patient suffers from a disorder characterized by depressive episodes, they are carried out in the current depressive episode.

[0021] As used in the context of the present invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician or other clinician, which biological or clinical response in humans includes alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0022] "Clinical response" includes, but is not limited to, improvements on rating scales that assess (i) a sleep disorder or aspect of a sleep disorder and / or (ii) a psychiatric or nervous system disorder or aspect of such a disorder.

[0023] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, which is a measure of symptom severity, treatment response, and treatment efficacy.

[0024] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the clinician's opinion (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0025] The CGI-Severity Scale (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in your patient?" This is rated on a 7-point scale: 1 = normal (no illness), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = very severe illness in patients.

[0026] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0027] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, the clinician compares the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of project entry (before medication was started), this patient's condition has improved greatly since treatment began: 1 = very much; 2 = very much; 3 = very little; 4 = no change from baseline (before treatment began); 5 = very little; 6 = very little; 7 = very little since treatment began."

[0028] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is a companion scale to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0029] In addition to the individual items of the scales as described herein, sub-combinations of the individual items may also be used to assess specific disease aspects.

[0030] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a predetermined amount of an active compound or pharmaceutical ingredient into a patient by any route. The active compound may be administered intravenously, intramuscularly, or subcutaneously.

[0031] As used in the context of this invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosing regimen" (or "administration regimen") shall mean a defined sequence of one or more individual administrations.

[0032] Sleep disorders There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Normal human sleep involves four to five cycles each night, with non-REM and REM sleep alternating during each cycle. Early in the night, non-REM sleep is deeper and occupies a disproportionately long time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle allocated to REM sleep.

[0033] Normal, healthy sleep consists of different phases, as outlined above, that progress in a sequential, tightly regulated sequence throughout the night.

[0034] When this tight regulation is disrupted, sleep disorders occur.

[0035] A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder. A sleep disorder affects a person's ability to function properly while awake.

[0036] Common forms of sleep disorders include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0037] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep; frequent awakenings during the night and difficulty falling asleep again; waking up too early in the morning or having unrefreshing sleep; and / or have at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, concentration problems, or accidents at work or while driving.

[0038] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. The transition from sleep to wakefulness is difficult. Individuals experiencing sleep drunkenness report awakenings accompanied by confusion, disorientation, sluggishness, and repeated returns to sleep.

[0039] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances resulting from a modulation of an individual's internal circadian rhythm or a mismatch between that circadian rhythm and desired or required work or social schedules. This dyssynchrony can be transient or persistent. The resulting clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are typically shortened and disrupted, performance during desired wakefulness is impaired, and intermittent attempts to return to a normal sleep schedule are unsuccessful.

[0040] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavior or physiological activity (such as sleepwalking or nightmares) that a person experiences before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0041] 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 (control center). One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea potentially has a significant impact on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation due to microarousals or awakenings. This can result in excessive daytime sleepiness.

[0042] In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0043] Not getting the right amount or quality of sleep can lead to personality changes, worsen existing mental disorders, and even trigger the onset of new ones. Sleep disorders can also interfere with cognitive function and lead to memory impairment. Sleep-deprived subjects may experience difficulty in decision-making, irritability, problems with executive function, and slow reaction times. Insomnia can also negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0044] Treatment for sleep disorders varies depending on the type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatment may also involve medication or psychotherapy.

[0045] Available treatments are not successful in all patients, may be associated with side effects, and / or may require prolonged treatment to achieve relevant therapeutic benefits.

[0046] For patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not always improve the sleep disorder.

[0047] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of the associated sleep disorders. While most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while others may cause sleep disorders.

[0048] Measurement of sleep disturbances Sleep can be assessed by measuring parameters such as sleep time, sleep architecture, sleep latency, and wake frequency and duration throughout the night. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency measurements, or using self-reported metrics (questionnaires).

[0049] Polysomnography is a procedure that requires patients to be monitored overnight in a specialized clinic, during which a variety of functions are measured, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0050] Another quantitative measurement method is actigraphy. To measure motor activity, an actimetry sensor is worn, which continuously records motor activity and is used to assess the sleep-wake cycle. This technique allows patients to continue their normal daily activities while the necessary data is recorded in a natural sleep environment.

[0051] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective metric for determining the time it takes a person to fall asleep during multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal; a mean sleep latency of less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Concomitant analysis of brain activity can aid in further diagnosis of sleep disorders.

[0052] Sleep assessment questionnaires collect assessments of components of sleep quality, such as perceived depth of sleep, difficulty waking, and restfulness after sleep, as well as assessments of other factors that may affect sleep quality, such as comorbid conditions and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep complaints often persist despite normal values ​​on quantitative measures of sleep.

[0053] Questionnaires may not only facilitate rapid and accurate assessment of complex clinical problems, but also help track patients' progress.

[0054] Various sleep quality indices are known. The following indices include examples of questionnaires that assess overall sleep, as well as questionnaires that assess insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. However, the present invention is not limited to the use of any particular index or questionnaire.

[0055] Some questionnaires rely on a recall period (recall window) of several days or weeks. This may be appropriate for diagnosing sleep disorders, but is not always appropriate for assessing the rapid onset of treatment effects, especially post-treatment effects. For some questionnaires, the recall period can be modified so that the scores obtained reflect the post-treatment period. To evaluate the effect of treatment on the sleep of patients suffering from specific conditions, the questionnaires specifically discussed herein rely on a recall period that begins after the acute hallucinatory experience after the last administration has subsided. To meet this criterion, the normally applied recall period is modified as necessary.

[0056] Sleep quality in general can be assessed using, for example, the Sleep-50 questionnaire.

[0057] The SLEEP-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and complaints and factors necessary for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a rating scale from 1 ("not at all true") to 4 ("very true") and asked to indicate how well the statement matches their experiences over the past month or another appropriate recall window.

[0058] To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but respondents must also meet a cutoff of at least 3 or 4 ("very true" or "very true," respectively) on subscales assessing the impact of sleep-related complaints on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0059] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0060] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other instruments include the Insomnia Severity Index, the Espie Sleep Disorders Index, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0061] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another appropriate recall window.

[0062] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0063] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Details of the Pittsburgh Sleep Quality Index scoring procedure can be found in the appendix to Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0064] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all domains. A cutoff score of 5 for the overall score distinguishes between those with and without sleep problems. A overall score of >5 indicates that the patient has severe difficulty in at least two domains or moderate difficulty in more than three domains.

[0065] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0066] The Insomnia Severity Inventory (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning, how significant the respondent perceives their insomnia compared to others, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (none) to 4 (very much); higher total scores correspond to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 means "subthreshold insomnia," 15–21 means "clinical insomnia (moderate severity)," and 22–28 means "clinical insomnia (severe)" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012, 2012). The recall window is 2 weeks. Other appropriate recall windows may also be used.

[0067] Successful treatment is indicated by (i) a decrease in score, for example by a decrease of >7 points, especially >8 points; and preferably (ii) a decrease below the cut-off for clinically significant insomnia.

[0068] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. With ratings for restlessness / agitation, mental hyperactivity, impact of insomnia, and lack of sleep preparation, the SDQ specifically relates to beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate the extent to which a particular statement about insomnia applies to their experience, with 1 meaning "not at all true" and 5 meaning "very true." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc. cit.;).

[0069] Successful treatment is indicated by a decrease in score.

[0070] The Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders Instrument is a universal measure for assessing sleep disorders. This instrument is available as a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulties related to falling asleep and staying asleep over a 7-day period.

[0071] Each item in the measure is rated on a 5-point scale. The raw scores of the items are summed to obtain a total raw score. The total raw score is then converted to a standardized T-score using a conversion table.

[0072] Successful treatment is indicated by a decrease in the T-score.

[0073] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0074] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stuck in traffic. Using a scale of 0 to 3 (0 meaning "never fall asleep" and 3 meaning "likely fall asleep"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 is identified as a level of daytime sleepiness that may become clinically problematic (A. Shahid et al., loc. cit.).

[0075] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0076] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment. The scale consists of only one item, requiring respondents to select one of seven statements that best describes their current perceived level of sleepiness. To assess sleepiness levels, a scale ranging from 1 (= energetic and active; alert; not feeling sleepy) to 7 (= drowsy; likely to fall asleep easily; unable to stay awake) is used.

[0077] Successful treatment is indicated by a decrease in score.

[0078] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0079] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists and rates the frequency of parasomnias and includes outcome measures (Arnulf et al., A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0080] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0081] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc. cit.;). An appropriate recall period can also be selected.

[0082] Successful treatment is indicated by a decrease in score.

[0083] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Scale. The 10-item questionnaire asks respondents to indicate how acutely the disorder has affected them during the past week using a Likert-type rating. Questions can be divided into one of two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep problems, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their experience of RLS on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least severe symptoms. Total scores can range from 0 to 40. As a brief measure with good psychometric quality, this instrument may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes. (A. Shahid et al., loc. cit.)

[0084] Treatment response can be assessed by a reduction in score.

[0085] Scales for assessing mental and nervous system disorders A number of scales have been proposed to assess the severity of psychiatric or neurological disorders, and these scales are based on tests that can be self-administered or administered by a clinician.

[0086] Scales for the assessment of psychiatric or neurological disorders that can be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring psychiatric or neurological disorders, which are discussed in more detail below.

[0087] Treatment outcomes are assessed using one or more indexes or scales at one or more time points after the end of the treatment course.

[0088] The assessment can be performed after the acute hallucinatory experience has subsided. A suitable time point for early assessment is generally about 2-3 hours after the last dose. Early assessment can typically be performed, for example, about 2 hours or about 3 hours after the last dose.

[0089] However, assessment of the effect on sleep disturbances, or on mental or nervous system disorders related to the effect on sleep disturbances, may be conducted as early as the day after treatment (i.e., Day 1) to allow the treated patient an opportunity to get at least one night's sleep.

[0090] Thus, evaluation on day 1 or evaluation on day 1 means evaluation on the day after dosing. Evaluation will occur no earlier than 12 hours after the last dose, and in any event no later than one night after the last dose and no later than 36 hours after the last dose. Evaluation can occur after approximately 24 hours.

[0091] Assessment on day 7 or assessment at day 7 refers to assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0092] For example, when using one of the scales to assess the severity of psychiatric or nervous system disorders to evaluate clinical response, if the clinical response is evaluated at an early time point (for example, 2 hours) after drug administration based on an endpoint made during a longer recall period (for example, usually 7 days for MADRS), a reasonable modification of such endpoint (for example, changing the MADRS recall period to 2 hours, and carrying forward the sleep items recorded at the baseline before drug administration) can be applied.Unless the recall period is specifically indicated, the same applies to any other scale used herein to evaluate the treatment effect on psychiatric or nervous system disorders.

[0093] At this early point, the considerations outlined apply because, on the one hand, the influence of the patient's condition before treatment on any scores recorded after treatment to assess clinical response should be kept as low as possible, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0094] At later time points (e.g., Day 1 or later), all items on the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0095] Resting-state networks and sleep disorders Brain processes can be studied by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0096] Functional brain images are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0097] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0098] Various resting-state networks have been identified and named primarily based on spatial similarities between resting-state networks and activity patterns seen in task-fMRI experiments.

[0099] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0100] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, which are associated with modulation of functional connectivity between one or more regions within a specific resting-state network and / or within one or more additional resting-state networks.

[0101] Modulation of the resting network can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0102] A key network involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during tasks and activated during rest. The DMN is involved in multiple cognitive processes, including higher cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, modulation of DMN activity is particularly relevant in relation to sleep disorders.

[0103] Disorders of the resting-state network have also been implicated in psychiatric or nervous system disorders, particularly disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), including bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive 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, rheumatoid arthritis, and rheumatoid arthritis. fibromyalgia, and migraine; mental and behavioral disorders due to psychoactive substance use, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia, Huntington's disease, Parkinson's disease; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia, dementia with Lewy bodies, vascular dementia, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; psychiatric or nervous system disorders associated with HIV, traumatic brain injury or post-COVID conditions.

[0104] Resting-state networks involved in sleep disorders are also influenced by mental or neurological conditions that are the result of certain medical conditions.

[0105] In patients with insomnia, dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain important regions that integrate emotional and bodily states, and that dysfunctional connectivity within these networks and / or between these networks and other brain regions may underlie patients' reduced vigilance, subjective distress, and sleep continuity.

[0106] The default mode network is affected in patients with hypersomnia: for example, idiopathic hypersomnia shows significant alterations in different DMN hubs—the precuneus and medial prefrontal cortex—and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0107] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disorders altered resting-state function in the cerebellum, which is involved in sleep regulation, and affected cognitive functions such as responsiveness and alertness. Furthermore, functional connectivity of the DMN was fundamentally different between morning- and evening-type circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may lead to alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases associated with circadian rhythm disorders.

[0108] Although functional brain imaging during a parasomnia event is technically challenging, precuneus differences have been observed in arousal disorders presenting with non-REM parasomnia.

[0109] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information, as well as monitoring movement. The precuneus is a subregion of the DMN. Therefore, the default mode network is affected in patients with parasomnia.

[0110] Resting-state fMRI studies in patients suffering from sleep-related breathing disorders such as central sleep apnea have shown significant deficits in global and regional connectivity, particularly in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0111] For example, sleep-related movement disorders such as periodic limb movements during sleep are reflected by modulation of the prefrontal motor control pathway, a subregion of the default mode network. Cerebellar and thalamic activity can also be observed, with additional activation of the red nucleus and brainstem.

[0112] In many cases, abnormal functional connectivity of resting-state networks involved in sleep disorders is also involved in the above-listed conditions. Thus, in accordance with the present invention, affecting these networks with therapies according to the present invention will improve sleep disorders and, if the treated patient suffers from a psychiatric or nervous system disorder, also improve that disorder.

[0113] Active Agent The above discussion indicates that sleep disorders themselves present a significant disease burden and deserve appropriate treatment.

[0114] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of sleep disorders and improve the condition overall.

[0115] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families, 5-HT1 through 5-HT7, with several subtypes, have been described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelic drugs" and are primarily characterized by their ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), while other effects such as sedation, narcosis, or hyperstimulation are minimal.

[0116] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0117] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and minor amine-associated receptors.

[0118] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0119] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a self-reported manic episode after ingesting psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0120] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0121] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0122] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from that of other hallucinogenic compounds.

[0123] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0124] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0125] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has enhanced affinity for the 5-HT1A receptor and acts as a potent agonist. Psilocin and DMT have an increased contribution to 5-HT2A binding compared to 5-MeO-DMT, with the latter of the three compounds showing the greatest difference between their affinities for 5-HT2A and 5-HT1A. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than the other two compounds.

[0126] 5-HT1A receptor agonism has been reported to reduce impulsivity and aggression, while 5-HT2A receptor agonism may short-term increase these same traits. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0127] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, psychotic disorders, e.g., schizophrenia, or personality disorders, e.g., schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0128] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate heavy use of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD).

[0129] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0130] Furthermore, antidepressants have been reported to induce isolated hypomanic events in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007):233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0131] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as a "loss of self"), often leading to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0132] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have investigated the efficacy of 5-MeO-DMT against recombinant human 5-HT7 receptors, as a radioligand, 3 Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM. The 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation.

[0133] Another characteristic of 5-MeO-DMT is its short half-life.

[0134] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0135] We investigated the pharmacokinetic properties of 5-MeO-DMT and found rapid absorption and distribution of inhaled 5-MeO-DMT, with peak concentrations and pharmacological effects observed during and immediately after administration.

[0136] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. Titrating doses as disclosed herein does not result in accumulation, and thus does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0137] The properties of 5-MeO-DMT make this compound particularly suitable for the treatment of sleep disorders, especially in patients suffering from psychiatric or nervous system disorders.

[0138] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0139] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0140] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0141] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

[0142] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0143] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0144] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Even more examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0145] Methods for preparing these compounds are known in the art.

[0146] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0147] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0148] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reference can be substituted with a 5-MeO-DMT prodrug or a salt thereof.

[0149] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0150] An example of a suitable organic moiety is —C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 and each R 1 , R2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0151] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 , and R 4 is defined as above.

[0152] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0153] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitriloacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitriloacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0154] Methods for preparing the prodrugs described herein are known in the art.

[0155] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0156] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0157] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenously, i.e., by intravenous injection.

[0158] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in formulations for administration by injection; examples of excipients and vehicles for such formulations are known in the art.

[0159] Dosing regimen The present invention also provides dose ranges, specific doses, and administration regimens (administration schemes), and suitable routes of administration.

[0160] The present invention is based in part on the inventors' conclusion that the occurrence of an acute hallucinogenic peak experience following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof causally facilitates, or at least serves as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from sleep disorders, particularly one or more of the aspects defined above.

[0161] Thus, achieving a peak experience more quickly, in a greater proportion of patients, and with greater reproducibility within each individual patient compared to previously tested hallucinogens, dosing regimens, and routes of administration would result in a superior therapeutic profile.

[0162] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no attenuation or disappearance of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily) designed to increase the incidence of peak experiences and thereby enhance therapeutic efficacy. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time), induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at that higher dose. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance at the patient population level.

[0163] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate and modulate the reproducibility of peak experiences, and to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the slow onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration), which may last for several days.

[0164] A patient suffering from a sleep disorder as defined herein is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0165] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (i.e., the patient is not receiving any other treatment for the sleep disorder).

[0166] The dose of 5-MeO-DMT administered to a patient suffering from a sleep disorder, as defined herein, is in the range of about 1 mg to about 10 mg, or any amount within that range, administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, and this weight amount can be calculated from the stated weight amount of 5-MeO-DMT free base, assuming an equimolar amount is used. 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. It should be noted that when a range, such as "about 1 mg to about 10 mg," is given herein, the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0167] In a preferred embodiment, the improved method for treating a patient suffering from a sleep disorder using a therapeutically effective amount of 5-MeO-DMT as defined herein comprises the occurrence of a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0168] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from a sleep disorder with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, comprising a clinical response occurring by about 2 hours after administration of 5-MeO-DMT, for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0169] In a preferred embodiment, the improved method for treating a patient suffering from a sleep disorder using a therapeutically effective amount of 5-MeO-DMT as defined herein comprises administering more than a single dose of 5-MeO-DMT.

[0170] In a preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 doses, the interval between each dose within each treatment block being at least about 1 hour and not more than about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0171] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0172] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0173] In one embodiment, the dose of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0174] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0175] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0176] For embodiments in which the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration will be 7 mg.

[0177] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration and to a dosage selected from about 7 mg to about 9 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific useful amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0178] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific useful amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0179] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 10 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic peak experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a hallucinogenic peak experience at an 8 mg dose, and therefore the highest dosage in the first treatment block was 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 8 mg.

[0180] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific useful 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.

[0181] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific useful 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.

[0182] Pharmaceutically acceptable salts of 5-MeO-DMT are preferably used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0183] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0184] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Mystical Experiences Questionnaire-Revised (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0185] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Feeling (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0186] In accordance with the present invention, the occurrence of a "Peak Hallucinatory Experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experiences Scale (PES) total score (also called the Peak Hallucinatory Experience Questionnaire (PPEQ)), which is the average of the patient's responses, scored on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control did it make you feel? 3. How profound (i.e., meaningful) was the experience?

[0187] Treatment of sleep disorders and mental and nervous system disorders According to the present invention, sleep disorders can be treated in patients suffering from idiopathic sleep disorders as well as psychiatric or nervous system disorders. In the case of patients suffering from sleep disorders associated with psychiatric or nervous system disorders, treatment of the sleep disorder according to the present invention leads to improvement of the condition related to the sleep disorder.

[0188] The resting state networks involved in sleep disorders are often also involved in the conditions listed above.

[0189] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption resets pathological, incomplete brain connections as the network rewires. New, healthy functional connections are established, with lasting effects.

[0190] The long-lasting effects can be explained by 5-MeO-DMT's neuroplasticity-promoting properties. 5-MeO-DMT promotes structural and functional plasticity, particularly at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, which initiates the formation of new synaptic connections. These new connections can be strengthened, weakened, or even eliminated, depending on activity.

[0191] The resulting new synapses then influence the pattern of neuronal activity, and we conclude that such reciprocal structural and functional modifications contribute to the proper establishment of networks and the persistence of effects following 5-MeO-DMT administration.

[0192] From a biochemical point of view, 5-MeO-DMT interacts specifically with the 5-HT receptor.

[0193] 5-HT receptors, receptors for the neurotransmitters serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A wide range of physiological and pathological functions are mediated through these receptors.

[0194] The brain expresses seven types of 5-HT receptors that can be further separated into several subtypes. The various types and subtypes exhibit distinct spatial distributions.

[0195] 5-MeO-DMT interacts with several 5-HT receptors, which mediate effects of 5-MeO-DMT on resting network and neuronal plasticity.

[0196] In addition to the 5-HT1A and 5-HT2A receptors, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0197] 5-HT7 receptors have roles in neurogenesis, synaptogenesis and dendritic spine formation, and are involved in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0198] 5-HT7 receptors are particularly expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0199] The suprachiasmatic nucleus (SNU) is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders revealed modulation of functional connectivity between the SNU and regions within the default mode network.

[0200] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the receptor's function in regulating the sleep / wake cycle, and the inventors believe this may allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0201] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as one mediator of the pharmacological effects of 5-MeO-DMT, including "resetting" the functional connectivity of networks and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0202] The inventors further believe that 5-MeO-DMT's binding to the 5-HT7 receptor, in addition to its binding to the 5-HT1A receptor, as two mediators of its effects, including "resetting" functional network connectivity and neuroplasticity, may also enable it to exert beneficial effects in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0203] Treatment according to the invention will improve the sleep disorder and, if the patient being treated suffers from a psychiatric or nervous system disorder, will also improve that disorder.

[0204] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) support that sleep disorders can be successfully treated with the administration of 5-MeO-DMT.

[0205] The TRD study, described in more detail in the Examples section below, assessed, among other things, the MADRS item "Decreased Sleep," which reflects insomnia.

[0206] The MADRS item "Decreased Sleep" describes the experience of a decrease in the duration or depth of sleep compared to the subject's normal pattern when healthy. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, shallow, or disrupted sleep. A score of 4 means reduced or interrupted sleep by at least 2 hours. A score of 6 means less than 2-3 hours of sleep.

[0207] Aggregate scores for the MADRS item "Decreased Sleep" across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 25. By day 1 of treatment (the earliest time point to assess the treatment's effect on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 of treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0208] The combined MADRS "Decreased Sleep" score across all four patients in the 12 mg group had a baseline of 12. On post-treatment day 1, the score decreased to 10, corresponding to a 2-point or 17% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0209] Thus, the score for the scale item "decreased sleep," which is particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat patients suffering from sleep disorders, particularly psychiatric or nervous system disorders.

[0210] Idiopathic sleep disorders Treating a patient suffering from an idiopathic sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the idiopathic sleep disorder.

[0211] Reduction or elimination of the idiopathic sleep disorder is observed 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0212] The reduction or elimination of sudden onset sleep disturbance preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0213] In one embodiment, the reduction or elimination of the sudden onset sleep disturbance is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0214] In the case of idiopathic sleep disorders, clinical response may be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least one level. Preferably, the CGI-S score is decreased by at least two levels and / or to a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three levels and / or to a score of 0.

[0215] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0216] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0217] The improvement in the idiopathic sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0218] In one embodiment, improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0219] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0220] Improvement in idiopathic sleep disturbance, as reflected by at least a "much improved" score on the CGI-I or PGI-I score, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0221] The improvement in the sleep disorder, as reflected by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0222] In one embodiment, improvement in the idiopathic sleep disorder, as reflected by a score of at least "much improved" on the CGI-I score or PGI-I score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0223] Improvement in the case of idiopathic sleep disorders can also be assessed by any other measure that reflects changes in the quality or quantity of sleep, such as the Pittsburgh Sleep Quality Index (PSQI), as described above.

[0224] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in the overall score, preferably (ii) a decrease to 5 or less. The applicable recall period begins after the acute hallucinatory experience following the last dose has subsided.

[0225] Improvement in the idiopathic sleep disorder, as reflected by a decrease in PSQI total score, particularly a decrease to 5 or less, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0226] Such improvement in the idiopathic sleep disorder, as reflected by a reduction in PSQI total score, particularly a reduction to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0227] Improvement in the idiopathic sleep disorder, as reflected by a decrease in PSQI total score, particularly a decrease to 5 or less, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0228] In one embodiment, improvement in idiopathic sleep disorders, as reflected by a reduction in PSQI total score, particularly a reduction to 5 or less, is observed at day 7, preferably by day 14, and more preferably by day 28.

[0229] Sleep disorders associated with mental and nervous system disorders Although sleep disorders may be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may suffer from, some psychiatric and nervous system disorders are associated with sleep disorders. In particular, the relationship between sleep and psychiatric or nervous system disorders is often bidirectional. Not only can psychiatric or nervous system disorders adversely affect healthy sleep patterns, but sleep disorders can also be a contributing factor to the onset, progression, and prognosis of mental health or nervous system disorders.

[0230] Treatment according to the present invention reduces or eliminates the sleep disorder and preferably also improves any associated psychiatric or neurological disorders.

[0231] Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0232] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0233] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present for the same two-week period and representing a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

[0234] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0235] During a depressive episode, patients often suffer from insomnia or hypersomnia.

[0236] Sleep disturbances are included as diagnostic criteria for disorders characterized by depressive episodes and may be assessed as part of the MADRS or HAM-D assessment.

[0237] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0238] The items are outward sadness; verbal sadness; internal tension; decreased sleep; decreased appetite; difficulty concentrating; inhibitions; inability to feel emotions; pessimistic thoughts; and suicidal thoughts. Each item is scored from 0 to 6. The total score ranges from 0 to 60.

[0239] The item "reduced sleep" reflects the experience of sleep disturbance, specifically a reduction in the duration or depth of sleep compared to the subject's own normal pattern when healthy. If the patient sleeps normally, a score of 0 is assigned. If the patient has mild difficulty falling asleep or mildly reduced, shallow, or interrupted sleep, a score of 2 is assigned. If sleep is reduced or interrupted for at least 2 hours, the score is 4. If sleep is less than 2-3 hours, the score is 6.

[0240] The Hamilton Rating Scale for Depression (HAM-D) allows clinicians to assess the nature and severity of mood disorders in patient populations. The scale consists of 21 survey items, but only the first 17 items (depressed mood; guilt; suicide; initial insomnia; nighttime insomnia; delayed insomnia; work and interest; retardation; agitation; mental anxiety; somatic anxiety; digestive somatic symptoms; general somatic symptoms; genital symptoms; hypochondriasis; weight loss; and insight) are used for scoring.

[0241] For most questions, scores range from 0 to 4, with 4 indicating more acute signs of depression. For some questions, the range extends only to 2. Total scores can be tallied and compared with previous scores or against a predefined cutoff score.

[0242] Early insomnia reflects insomnia during the early hours of the night. If the patient has no difficulty falling asleep, the score is 0; if the patient complains of occasional difficulty falling asleep, i.e., difficulty falling asleep for more than 30 minutes, the score is 1; if the patient complains of difficulty falling asleep every night, the score is 2.

[0243] Nighttime, i.e., midnight, insomnia is scored as 0 if there is no difficulty; 1 if the patient complains of being restless and agitated during the night, and 2 if the patient wakes during the night (getting out of bed for reasons other than urination is rated as 2).

[0244] Delayed insomnia reflects insomnia before dawn. If there is no difficulty, the score is 0; if the patient wakes up before dawn but goes back to sleep, it is 1; if the patient gets out of bed and is unable to fall asleep again, it is 2.

[0245] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity are observed within and / or between multiple brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal.

[0246] Treating patients suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the disorder characterized by depressive episodes.

[0247] The reduction or elimination of sleep disturbances in a patient suffering from a disorder characterized by a depressive episode is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0248] In patients suffering from a disorder characterized by a depressive episode, the reduction or elimination of sleep disturbances occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0249] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from a disorder characterized by a depressive episode is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0250] Improvement in sleep disturbance in patients suffering from a disorder characterized by depressive episodes, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0251] The improvement in sleep disturbance in patients suffering from a disorder characterized by a depressive episode, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients suffering from a disorder characterized by a depressive episode, as reflected by a decrease in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0252] In one embodiment, improvement in sleep disturbance in patients suffering from a disorder characterized by depressive episodes, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0253] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from a disorder characterized by a depressive episode is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0254] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the sleep reduction score on the MADRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the sleep reduction score on the MADRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, a reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the MADRS item sleep reduction score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0256] Reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by a depressive episode is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0257] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0258] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in PSQI score, particularly a decrease to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0259] As mentioned above, sleep disorder is closely related to the disorder characterized by depressive episodes.Therefore, the improvement of sleep disorder also leads to the improvement of the disorder characterized by depressive episodes.Sleep disorder also affects other aspects of the disorder characterized by depressive episodes, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of the disorder characterized by depressive episodes.

[0260] Improvement in a disorder characterized by a depressive episode in a patient who also suffers from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0261] Improvement in the disorder characterized by depressive episodes in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the disorder characterized by depressive episodes in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0262] In one embodiment, improvement in a disorder characterized by depressive episodes in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0263] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest, which affect the way a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0264] The patient may have moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. It is further contemplated that the patient may have severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or greater.

[0265] Patients suffering from MDD may suffer from a treatment-resistant (TRD) form of the disorder.

[0266] In patients with MDD, dysfunctional connectivity and regulation is observed within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0267] As mentioned above, connectivity dysfunction in the resting network is also associated with sleep disorders such as insomnia and hypersomnia.

[0268] An estimated three-quarters of all patients with MDD suffer from some form of sleep disorder, such as insomnia or hypersomnia, sometimes both in the same episode. Under DSM-5 criteria, sleep disturbance is one of nine symptoms, at least five of which must be present over a given period of time, to meet the diagnosis of MDD.

[0269] Sleep disturbances in the context of MDD are associated with an increased risk of suicide and a significantly reduced quality of life for patients.

[0270] Treating patients suffering from MDD and associated sleep disorders, including treatment-resistant forms of MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement in the MDD.

[0271] The reduction or elimination of sleep disturbances in a patient with MDD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0272] The reduction or elimination of sleep disturbances in patients with MDD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0273] In one embodiment, the reduction or elimination of sleep disturbances in a patient with MDD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0274] Improvement in sleep disturbance in patients with MDD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0275] Improvement in sleep disturbance in patients with MDD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with MDD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0276] In one embodiment, improvement in sleep disturbance in patients with MDD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0277] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with MDD is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0278] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with MDD, as reflected by at least an improvement in the sleep reduction score on the MADRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with MDD, as reflected by at least an improvement in the sleep reduction score on the MADRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0279] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with MDD, as reflected by an improvement in the MADRS item sleep deprivation score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0280] Reduction or elimination of sleep disturbances in patients with MDD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0281] The reduction or elimination of sleep disturbances in patients with MDD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with MDD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0282] In one embodiment, reduction or elimination of sleep disturbances, particularly decreased sleep, in patients with MDD, as reflected by an improvement in PSQI score, particularly a decrease to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0283] As mentioned above, sleep disorder is closely related to MDD.Therefore, the improvement of sleep disorder also leads to the improvement of MDD.Sleep disorder also affects other aspects of MDD, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of MDD.

[0284] Improvement in major depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0285] Improvement in major depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in major depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0286] In one embodiment, improvement in MDD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0287] Sleep disorders are also associated with postpartum depression (PPD).

[0288] More than 50% of women may experience a short-term period of depressed or tearful mood after giving birth. However, a subset of women may develop PPD - a debilitating mood disorder that occurs during pregnancy or within four weeks after delivery. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0289] The patient may have moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. It is further contemplated that the patient may have severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0290] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0291] Additionally, patients treated according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0292] Additionally, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0293] Patients with PPD may suffer from a treatment-resistant form of the disorder.

[0294] Depression during the postpartum period not only affects the mother's overall health, but also the way the mother and baby communicate and ultimately the way the baby develops.

[0295] Sleep disturbances are a commonly reported symptom during pregnancy and are highly associated with the presence of depressive symptoms: women with poor sleep quality are 3.34 times more likely to suffer from depression than women with good sleep quality.

[0296] The presence of sleep disturbances during pregnancy is itself a predictor of PPD.

[0297] Studies have shown that changes in sleep quality, but not hormonal milieu, are associated with the recurrence and severity of PPD.

[0298] PPD can be assessed by the Edinburgh Postnatal Depression Scale (EPDS), a scale that assesses how the mother has felt over the past seven days. Insomnia as a result of discomfort is one of the 10 questions assessed by the questionnaire. Ratings range from "0" (no, not at all) to "3" (yes, most of the time). With a threshold level of a total score of 13, sleep disturbances can be considered a fundamental part of the PPD diagnosis.

[0299] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with dysfunction in resting-state network connectivity within and / or between, for example, the default mode network and the frontoparietal network.

[0300] Treating patients suffering from PPD and associated sleep disorders, including treatment-resistant forms of PPD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, leading to improvement of the PPD.

[0301] The reduction or elimination of sleep disturbances in a patient with PPD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0302] The reduction or elimination of sleep disturbances in patients with PPD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0303] In one embodiment, the reduction or elimination of sleep disturbances in a patient with PPD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0304] Improvement in sleep disturbance in patients with PPD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0305] Improvement in sleep disturbance in patients with PPD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with PPD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0306] In one embodiment, improvement in sleep disturbance in patients with PPD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0307] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with PPD is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0308] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with PPD, as reflected by an improvement in the sleep reduction score on the MADRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with PPD, as reflected by an improvement in the sleep reduction score on the MADRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0309] In one embodiment, a reduction or elimination of sleep disturbances, particularly sleep reduction, in a patient with PPD, as reflected by an improvement in the MADRS item sleep reduction score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0310] Reduction or elimination of sleep disturbances in patients with PPD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0311] The reduction or elimination of sleep disturbances in patients with PPD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with PPD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0312] In one embodiment, the reduction or elimination of sleep disturbances, particularly decreased sleep, in patients with PPD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0313] As mentioned above, sleep disorder is closely related to PPD.Therefore, the improvement of sleep disorder also leads to the improvement of PPD.Sleep disorder also affects other aspects of PPD, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of PPD.

[0314] Improvement in postpartum depression in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0315] Improvement in postpartum depression in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in postpartum depression in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0316] In one embodiment, improvement in PPD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0317] In one embodiment, improvement in PPD in patients who also suffer from an associated sleep disorder, as reflected by improvement in the Edinburgh Postnatal Depression Scale (EPDS), is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0318] Sleep disorders further impair maternal function.

[0319] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index was designed to measure functioning in the year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score of 0 to 6, with a maximum total score of 120. Higher scores indicate better maternal functioning.

[0320] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-infant communication, maternal emotional well-being, social support, control, and adjustment.

[0321] A BIMF score of 95 or less is considered herein to represent a mild impairment of maternal functioning, a score of 80 or less is considered herein to represent a severe impairment of maternal functioning, and a score of 65 or less is considered herein to represent a severe impairment of maternal functioning.

[0322] The inventors have determined that elevated scores on the MADRS item "reduced sleep" negatively impact both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "reduced sleep" impair self-care, emotional well-being and control.

[0323] Increased scores on the MADRS item sleep decrement impair emotional well-being, social support, and control. Conversely, improvements on this MADRS item translate to improved maternal functioning, particularly in the BIMF functional domains of self-care, emotional well-being, and / or control.

[0324] The inventors conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in sleep disturbances, particularly reduction or elimination of sleep reduction.

[0325] We further conclude that the reduction or elimination of decline by treating PPD patients leads to improved maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score.

[0326] The BIMF total score improves by 10% or more, preferably 20% or more.

[0327] Improvement in maternal function in patients with PPD is reflected by at least an improvement in the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] Improvement in maternal function in patients with PPD, as reflected by at least an improvement in BIMF total score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function, as reflected by at least an improvement in BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0329] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed when depression is present for most days of the day for at least two years. Symptom-free periods last less than two months.

[0330] During depression, two or more of the following must be present: 1. Hopelessness; 2. Low energy or fatigue; 3. Low self-esteem; 4. Decreased (insomnia) or increased (hypersomnia) sleep; 5. Loss of appetite or overeating; 6. Difficulty making decisions or poor concentration.

[0331] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0332] In patients with persistent depressive disorder, altered functional connectivity is observed within and / or between multiple brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Connectivity dysfunction is observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0333] Treatment of patients suffering from persistent depressive disorder, including treatment-resistant forms of persistent depressive disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the persistent depressive disorder.

[0334] The reduction or elimination of sleep disturbances in patients with persistent depressive disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0335] In patients with persistent depressive disorder, the reduction or elimination of sleep disturbances occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0336] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from persistent depressive disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0337] Improvement in sleep disturbance in patients with persistent depressive disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0338] Improvement in sleep disturbance in patients with persistent depressive disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with persistent depressive disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0339] In one embodiment, improvement in sleep disturbance in patients with persistent depressive disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0340] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with persistent depressive disorder is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0341] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from persistent depressive disorder, as reflected by at least an improvement in the sleep reduction score on the MADRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from persistent depressive disorder, as reflected by at least an improvement in the sleep reduction score on the MADRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] In one embodiment, a reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with persistent depressive disorder, as reflected by an improvement in the MADRS item sleep reduction score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0343] Reduction or elimination of sleep disturbances in patients with persistent depressive disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] The reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] In one embodiment, the reduction or elimination of sleep disturbances, particularly decreased sleep, in patients with persistent depressive disorder, as reflected by an improvement in PSQI score, particularly a decrease to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0346] As mentioned above, sleep disorder is closely related to persistent depressive disorder.Therefore, the improvement of sleep disorder is also connected to the improvement of persistent depressive disorder.Sleep disorder also affects other aspects of persistent depressive disorder, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of persistent depressive disorder.

[0347] Improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] Improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0349] In one embodiment, improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0350] Sleep disturbances are also a common symptom of seasonal affective disorder.

[0351] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms often beginning in the fall and remitting in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0352] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0353] People with seasonal affective disorder often feel excessively sleepy during the day, sleep longer than usual at night, have difficulty waking from long periods of sleep, or may find that naps do not relieve sleepiness, and feel the need to take repeated naps throughout the day. Nightmares are also common in people with seasonal affective disorder.

[0354] Month- and season-dependent sleep duration is a core component of the assessment of seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire (SPAQ), whereby subjects are asked to rate the seasonal changes they have experienced in sleep, socialization, mood, weight, appetite, and energy, whereby sleep is assessed in three of six questions.

[0355] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0356] In patients with seasonal affective disorder, altered functional connectivity is observed within and / or between multiple brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Dysfunction in connectivity is observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0357] Treatment of patients suffering from seasonal affective disorder, including treatment-resistant forms of seasonal affective disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the seasonal affective disorder.

[0358] The reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] The reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0360] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0361] Improvement in sleep disturbances in patients with seasonal affective disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0362] The improvement in sleep disturbance in patients with seasonal affective disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with seasonal affective disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0363] In one embodiment, improvement in sleep disturbance in patients with seasonal affective disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0364] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0365] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from seasonal affective disorder, as reflected by an improvement in the sleep reduction score on the MADRS items, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients suffering from seasonal affective disorder, as reflected by an improvement in the sleep reduction score on the MADRS items, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] In one embodiment, a reduction or elimination of sleep disturbances, particularly sleep reduction, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the MADRS item sleep reduction score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0367] Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0368] The reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0369] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with seasonal affective disorder, as reflected by an improvement in PSQI score, particularly a decrease to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0370] As mentioned above, sleep disorder is closely related to seasonal affective disorder.Therefore, the improvement of sleep disorder can also lead to the improvement of seasonal affective disorder.Sleep disorder also affects other aspects of seasonal affective disorder, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, can further contribute to the overall improvement of seasonal affective disorder.

[0371] Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0373] In one embodiment, improvement in seasonal affective disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

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

[0375] Patients with BD may suffer from treatment-resistant forms of the disorder.

[0376] If there has been at least one manic episode with or without a depressive episode, BD is classified as bipolar I disorder. If there has been at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode, BD is classified as bipolar II disorder. If these symptoms are due to drugs or medical problems, it is not diagnosed as bipolar disorder.

[0377] In particular, patients suffering from BD, whether diagnosed with bipolar II disorder or bipolar I disorder, are suffering from a current major depressive episode.

[0378] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient's total score can be 19 or higher, e.g., 24 or higher, particularly 37 or higher.

[0379] Alternatively, or in addition, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as 24 or greater, particularly 37 or greater.

[0380] Sleep disorders, including variations in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities, are particularly prevalent in patients with BD, including bipolar I disorder and bipolar II disorder.

[0381] A decreased need for sleep is often an indicator of the onset of a manic episode.

[0382] Disruption of the normal sleep-wake cycle has been implicated in the psychopathology of bipolar disorder, and dysregulation of the circadian system has been considered a biomarker for bipolar disorder.

[0383] During a manic episode, sleep disturbances are present in 69–99% of patients.

[0384] Sleep disorders contribute to early recurrence of episodes and reduced quality of life (including reduced healthy behavior and increased risk of suicide).

[0385] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated for clinical use by trained raters. BDRS items are based on a clinical interview and assess the severity of depressive and / or mixed symptoms exhibited by the patient during the current and past few days. If there is a discrepancy between current and past few days' symptoms, the current symptoms should be reflected in the assessment. The scale contains 20 questions, with a maximum possible score of 60. Higher scores indicate greater severity.

[0386] Questions address depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; flat affect; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor impulsivity; increased speech; and agitation.

[0387] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3.

[0388] Sleep disorders (sleep dysregulation) are assessed based on changes in total sleep over a 24-hour cycle, independent of external factors. Sleep disorders can take the form of either insomnia (a decrease in total sleep time) or hypersomnia (an increase in total sleep time, including daytime sleep).

[0389] The assessment of insomnia (reduction in total sleep time) included a score of 0 (no reduction in total sleep time); a score of 1 (mild, reduction of up to 2 hours); a score of 2 (moderate, 2-4 hours); and a score of 3 (severe, more than 4 hours).

[0390] Alternative ratings for hypersomnia (increased total sleep time, including daytime sleep) include a score of 0 (no increase in total sleep time, including daytime sleep); a score of 1 (mild, less than 2 hours or normal amount but not restorative); a score of 2 (moderate, 2-4 hours); and a score of 3 (severe, more than 4 hours).

[0391] Patients with bipolar disorder exhibit abnormal intrinsic organization and interconnectivity of resting-state networks. Compared with healthy controls, resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network. In particular, altered functional connectivity within the default mode network has also been observed in patients with sleep disorders.

[0392] Treating patients suffering from BD and associated sleep disorders, including treatment-resistant forms of BD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, leading to improvement of BD.

[0393] Reduction or elimination of sleep disturbances in patients with BD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0394] The reduction or elimination of sleep disturbances in patients with BD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0395] In one embodiment, the reduction or elimination of sleep disturbances in a patient with BD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0396] Improvement in sleep disturbance in patients with BD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0397] Improvement in sleep disturbance in patients with BD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with BD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0398] In one embodiment, improvement in sleep disturbance in patients with BD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0399] Reduction or elimination of sleep disturbances in a patient with BD may be reflected by at least an improvement in the sleep disturbance score on the BDRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0400] The reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in the sleep disturbance score on the BDRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in the sleep disturbance score on the BDRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0401] In one embodiment, a reduction or elimination of sleep disturbances in a patient with BD, as reflected by an improvement in the sleep disturbance score on the BDRS item, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0402] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with BD is reflected by at least an improvement in the sleep deprivation score on the MADRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0403] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with BD, as reflected by an improvement in the MADRS item sleep reduction score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with BD, as reflected by an improvement in the MADRS item sleep reduction score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0404] In one embodiment, reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with BD, as reflected by an improvement in the MADRS item sleep deprivation score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0405] Reduction or elimination of sleep disturbances in patients with BD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0406] The reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0407] In one embodiment, a reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0408] Reduction or elimination of sleep disturbances, particularly an increase in total sleep time, in a patient with BD is reflected by an improvement in the hypersomnia score on the BDRS item 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0409] The reduction or elimination of sleep disturbances, particularly increases in total sleep time, in patients with BD, as reflected by an improvement in the hypersomnia score on the BDRS item, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances, particularly increases in total sleep time, in patients with BD, as reflected by an improvement in the hypersomnia score on the BDRS item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] In one embodiment, a reduction or elimination of sleep disturbances, particularly an increase in total sleep time, in a patient with BD, as reflected by an improvement in the hypersomnia score on the BDRS item, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0411] As mentioned above, sleep disorder is closely related to BD.Therefore, improving sleep disorder can also lead to the improvement of BD.Because sleep disorder also affects other aspects of BD, the inventors conclude that improving sleep disorder can also contribute to the overall improvement of BD.

[0412] Improvement in BD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0413] Improvement in BD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0414] In one embodiment, improvement in BD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0415] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system that is related to preparation for anticipated events or situations that are perceived as threatening.

[0416] Patients suffering from an anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0417] Patients suffering from anxiety disorders often experience sleep disturbances, particularly insomnia. Excessive worry and fear can make it difficult to fall asleep and stay asleep throughout the night.

[0418] Insomnia can exacerbate anxiety, leading to a vicious cycle of insomnia and anxiety.

[0419] The severity of anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A). This scale consists of 14 items, each defined by a set of symptoms, measuring both mental anxiety (mental agitation and psychological distress) and somatic anxiety (physical problems related to anxiety). Item 4 is "insomnia," defined as "difficulty falling asleep, sleep disruption, unrest, and awakening fatigue, dreams, nightmares, or night terrors." Each item is scored on a scale of 0 (absent) to 4 (severe), with a total score ranging from 0 to 56.

[0420] Sleep disorders can also be assessed using, for example, the Pittsburgh Sleep Quality Index (PSQI) total score.

[0421] Anxiety disorders are associated with alterations in the functional connectivity of resting-state networks. Anxiety disorders exhibit abnormalities in the default mode network (DMN), which influences self-perception, the salience network (SN), which controls emotion / anxiety, and the somatomotor network (SMN), which is responsible for body awareness. The resting-state balance within and / or between these networks, e.g., the SMN and SN, relative to the DMN, may be abnormal in various anxiety disorders.

[0422] Modulation of functional connectivity in affected networks is also associated with sleep disturbances, and anxiety disorders are associated with sleep disturbances.

[0423] Treatment of patients suffering from anxiety disorders, including treatment-resistant forms of anxiety disorders, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the anxiety disorder.

[0424] The reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0425] The reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0426] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0427] Improvement in sleep disturbance in patients suffering from an anxiety disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0428] The improvement in sleep disturbance in a patient suffering from an anxiety disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in a patient suffering from an anxiety disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0429] In one embodiment, improvement in sleep disturbance in a patient suffering from an anxiety disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0430] Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0431] The reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0432] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0433] As mentioned above, sleep disorder occurs in patients with anxiety disorder.Therefore, improving sleep disorder also leads to improving anxiety disorder.Because sleep disorder also affects other aspects of anxiety disorder, the inventors conclude that improving sleep disorder also contributes to the overall improvement of anxiety disorder.

[0434] Improvement in the anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0435] Improvement in the anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0436] In one embodiment, improvement in the anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0437] Separation anxiety disorder is characterized by excessive anxiety about separation from home and / or from people to whom the sufferer has strong emotional attachments.

[0438] The separation situation can be very distressing for the patient, and the separation can make it difficult for them to go to school or work. Patients with separation anxiety disorder can also have excessive anxiety about unwanted events happening to important people in their lives, such as family members.

[0439] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0440] Separation anxiety disorder is associated with sleep disturbances, which are also part of the diagnostic criteria for separation anxiety disorder. Sleep disturbances in patients with separation anxiety disorder include nightmares, difficulty falling asleep or staying asleep, early awakenings, and parasomnias.

[0441] The severity of separation anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0442] Sleep disturbances in separation anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0443] Anxiety disorders are associated with alterations in the functional connectivity of resting-state networks. Anxiety disorders exhibit abnormalities in the default mode network (DMN), which influences the sense of self; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for bodily awareness. The resting-state balance within and / or between these networks, e.g., the SMN and SN, relative to the DMN, may be abnormal in various anxiety disorders.

[0444] Modulation of functional connectivity in affected networks is also associated with sleep disturbances, and separation anxiety disorder is associated with sleep disturbances.

[0445] Treatment of patients suffering from separation anxiety disorder, including treatment-resistant forms of separation anxiety disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the separation anxiety disorder.

[0446] The reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0447] The reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0449] Improvement in sleep disturbance in patients with separation anxiety disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] The improvement in sleep disturbance in patients with separation anxiety disorder, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with separation anxiety disorder, as reflected by a decrease in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0451] In one embodiment, improvement in sleep disturbance in patients with separation anxiety disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0452] Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] The reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0455] As mentioned above, sleep disturbance is a significant complaint of patients with separation anxiety disorder.Therefore, improving sleep disturbance also leads to the improvement of separation anxiety disorder.Because sleep disturbance also affects other aspects of separation anxiety disorder, the inventors conclude that improving sleep disturbance, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of separation anxiety disorder.

[0456] Improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] Improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0458] In one embodiment, improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0459] Agoraphobia is the fear of situations or places that can cause feelings of panic, claustrophobia, helplessness, or embarrassment.

[0460] Patients with agoraphobia may find it difficult to leave the house. The thought of leaving the house can cause considerable anxiety, even to the point of avoidance. Fear of crowds, travel, elevators, movie theaters, shopping malls, etc. can cause significant problems.

[0461] Patients with agoraphobia may also have recurrent panic attacks.

[0462] Patients suffering from agoraphobia may suffer from a treatment-resistant form of the disorder.

[0463] Agoraphobia is associated with sleep disorders such as insomnia.

[0464] The severity of agoraphobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0465] Sleep disturbance in agoraphobia can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0466] Functional magnetic resonance imaging in individuals with agoraphobia reveals modulation of functional connectivity within and / or between resting-state networks involved in anxiety.

[0467] Treatment of patients suffering from agoraphobia, including treatment-resistant forms of agoraphobia, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of agoraphobia.

[0468] The reduction or elimination of sleep disturbances in a patient suffering from agoraphobia is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0469] The reduction or elimination of sleep disturbances in a patient suffering from agoraphobia occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from agoraphobia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0470] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from agoraphobia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0471] Improvement in sleep disturbance in patients with agoraphobia, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] The improvement in sleep disturbance in patients with agoraphobia, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with agoraphobia, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0473] In one embodiment, improvement in sleep disturbance in a patient suffering from agoraphobia, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0474] Reduction or elimination of sleep disturbances in a patient suffering from agoraphobia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] The reduction or elimination of sleep disturbances in a patient suffering from agoraphobia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from agoraphobia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0476] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from agoraphobia, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0477] As mentioned above, sleep disturbance is a significant complaint of patients with agoraphobia. Therefore, improving sleep disturbance also leads to improvement of agoraphobia. Because sleep disturbance also affects other aspects of agoraphobia, the inventors conclude that improving sleep disturbance, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of agoraphobia.

[0478] Improvement in agoraphobia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0479] Improvement in agoraphobia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in agoraphobia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0480] In one embodiment, improvement in agoraphobia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0481] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry about a wide range of situations and problems. People with GAD may anticipate disasters or worry excessively about money, health, family, work, or other problems.

[0482] Generalized anxiety disorder is diagnosed when an individual experiences persistent worry about everyday challenges that is disproportionate to the perceived threat. Patients with GAD typically experience excessive fear that can last for months to years.

[0483] GAD interferes with social, occupational, or other important areas of functioning.

[0484] Patients with GAD may suffer from a treatment-resistant form of the disorder.

[0485] A key feature of GAD is sleep disturbance, particularly difficulty falling asleep or staying asleep, or restless, unrestful sleep. Sleep disturbance is associated with significant impairment in GAD. In the DSM-5 criteria, sleep disturbance is one of six symptoms, at least three of which must be present in a given period to meet the diagnosis of GAD.

[0486] The severity of generalized anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0487] Sleep disturbances in generalized anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0488] Patients with GAD also show altered functional connectivity, particularly within the default mode network. Altered functional connectivity in affected networks is also associated with sleep disturbances.

[0489] Treating patients suffering from GAD and associated sleep disorders, including treatment-resistant forms of GAD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, leading to improvement in the GAD.

[0490] The reduction or elimination of sleep disturbances in a patient with GAD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0491] The reduction or elimination of sleep disturbances in patients with GAD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with GAD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0492] In one embodiment, the reduction or elimination of sleep disturbances in a patient with GAD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0493] Improvement in sleep disturbance in patients with GAD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] Improvement in sleep disturbance in patients with GAD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with GAD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0495] In one embodiment, improvement in sleep disturbance in patients with GAD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0496] Reduction or elimination of sleep disturbances in patients with GAD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0497] The reduction or elimination of sleep disturbances in patients with GAD, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with GAD, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] In one embodiment, a reduction or elimination of sleep disturbances in a patient with GAD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0499] As mentioned above, sleep disorder is one of the most common main complaints of patients with GAD.Therefore, improving sleep disorder also leads to the improvement of GAD.Sleep disorder also affects other aspects of GAD, so the inventors conclude that improving sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of GAD.

[0500] Improvement in GAD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0501] Improvement in GAD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in GAD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] In one embodiment, improvement in GAD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0503] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety. SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations, which can impair school, work, or relationships.

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

[0505] Sleep disturbances are very common in patients with social anxiety disorder, given the bidirectional relationship between sleep disturbances (mainly insomnia) and anxiety.

[0506] The severity of social anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0507] Sleep disturbances in social anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0508] Insomnia is reflected by alterations in functional connectivity within and / or between resting-state networks, such as the default mode network and salience network, in which alterations in functional connectivity are observed in patients with SAD.

[0509] Treating patients suffering from SAD, including treatment-resistant forms of SAD, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, leading to improvement of the SAD.

[0510] The reduction or elimination of sleep disturbances in a patient with SAD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0511] The reduction or elimination of sleep disturbances in a patient with SAD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient with SAD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0512] In one embodiment, the reduction or elimination of sleep disturbances in a patient with SAD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0513] Improvement in sleep disturbance in patients with SAD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0514] The improvement in sleep disturbance in patients with SAD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with SAD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0515] In one embodiment, improvement in sleep disturbance in patients with SAD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0516] Reduction or elimination of sleep disturbances in patients with SAD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0517] The reduction or elimination of sleep disturbances in patients with SAD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with SAD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] In one embodiment, a reduction or elimination of sleep disturbances in a patient with SAD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0519] As mentioned above, sleep disorder is a particularly important symptom in patients with SAD.Therefore, the improvement of sleep disorder also leads to the improvement of SAD.Sleep disorder also affects other aspects of SAD, so the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of SAD.

[0520] Improvement in SAD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0521] Improvement in SAD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0522] In one embodiment, improvement in SAD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0523] Patients with panic disorder experience sudden, spontaneous panic attacks of intense fear or discomfort that peak within minutes.

[0524] Panic attacks are characterized by many somatized anxiety symptoms, including sweating, trembling, shaking, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0525] Additionally, the disorder can often be characterized by anxiety about future panic attacks, and patients can become very preoccupied with fear of recurrent attacks.

[0526] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0527] Sleep disorders, particularly insomnia and hypersomnia, are very common in patients with panic disorder.

[0528] Patients with panic disorder may also experience nocturnal panic attacks, which are distinct from night terrors. Nocturnal panic attacks may occur unprovoked and often make it difficult to fall asleep again.

[0529] The severity of panic disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a metric for the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0530] Sleep disturbances in panic disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0531] Patients with panic disorder exhibit alterations in functional connectivity within and / or between the default mode network and the somatomotor network. Alterations in functional connectivity within and / or between resting-state networks, particularly in the default mode network, also characterize insomnia and hypersomnia.

[0532] Treatment of patients suffering from panic disorder, including treatment-resistant forms of panic disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the panic disorder.

[0533] The reduction or elimination of sleep disturbances in a patient suffering from panic disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0534] The reduction or elimination of sleep disturbances in patients suffering from panic disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from panic disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from panic disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0536] Improvement in sleep disturbance in patients suffering from panic disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] The improvement in sleep disturbance in patients suffering from panic disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients suffering from panic disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0538] In one embodiment, improvement in sleep disturbance in patients suffering from panic disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0539] Reduction or elimination of sleep disturbances in patients suffering from panic disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0540] The reduction or elimination of sleep disturbances in patients suffering from panic disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from panic disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0541] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from panic disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0542] As mentioned above, sleep disorder is very common in patients with panic disorder.Therefore, improving sleep disorder can also lead to the improvement of panic disorder.Because sleep disorder also affects other aspects of panic disorder, the inventors conclude that improving sleep disorder, especially the reduction or elimination of insomnia and / or hypersomnia, can further contribute to the overall improvement of panic disorder.

[0543] Improvement in panic disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] Improvement in panic disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in panic disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] In one embodiment, improvement in panic disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0546] A phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation. Patients suffering from a phobia experience extreme anxiety when anticipating or being exposed to the feared stimulus. There are animal-type (spiders, snakes, dogs) phobias, environmental-type (tornadoes, heights, water, fire) phobias, blood-injection-type (needles, medical procedures) phobias, situational-type (flying in an airplane, enclosed spaces) phobias, and other types of phobias (phobias that do not fit into any of the aforementioned categories).

[0547] Phobias typically result in a rapid onset of fear, usually present for more than six months. Patients go to great lengths to avoid the feared stimulus. The fear and avoidance cause significant distress and / or impairment in occupational, academic, or social functioning.

[0548] Patients suffering from phobias may suffer from treatment-resistant forms of the disorder.

[0549] There is evidence that patients with phobias are more likely to have sleep disorders.

[0550] The severity of phobias can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0551] Sleep disturbance in phobias can also be assessed by the Pittsburgh Sleep Quality Inventory (PSQI).

[0552] Phobias are also reflected in modulation of functional connectivity in resting-state networks, such as networks involving the amygdala and insular cortex, e.g., the salience network, which also plays a role in insomnia.

[0553] Treatment of patients suffering from phobias, including treatment-resistant forms of phobias, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the phobia.

[0554] The reduction or elimination of sleep disturbances in a patient suffering from a phobia is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0555] The reduction or elimination of sleep disturbances in a patient suffering from a phobia occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from a phobia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from a phobia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0557] Improvement in sleep disturbance in patients suffering from phobia, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0558] The improvement in sleep disturbance in a patient suffering from a phobia, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in a patient suffering from a phobia, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] In one embodiment, improvement in sleep disturbance in a patient suffering from a phobia, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0560] Reduction or elimination of sleep disturbances in patients suffering from phobias is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] The reduction or elimination of sleep disturbances in a patient suffering from a phobia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from a phobia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from a phobia, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0563] As mentioned above, the possibility of sleep disturbance is increased in patients with phobia.Therefore, improving sleep disturbance also leads to improvement of phobia.Because sleep disturbance also affects other aspects of phobia, the inventors conclude that improving sleep disturbance, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of phobia.

[0564] Improvement in phobia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0565] Improvement in phobia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in phobia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] In one embodiment, improvement in phobia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0567] Substance / drug-induced anxiety disorder is an anxiety disorder in which anxiety or panic occurs after use of alcohol, drugs of abuse, or medication, or after exposure to a toxin. Substance / drug-induced anxiety disorder results in prominent symptoms of panic or anxiety and can occur during the intoxication or withdrawal phase of substance or drug use.

[0568] The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0569] While taking the substance or medication, or within a short time after taking it, individuals suffering from substance / drug-induced anxiety disorder may feel tense and anxious, may experience symptoms of negative thinking, may have problems concentrating or remembering, may have fears of being out of control or psychotic or of dying, may lose weight due to gastrointestinal problems, may have chills, hot flashes, sweating, trembling, numbness or palpitations, difficulty breathing, difficulty swallowing, or chest pain.

[0570] Patients suffering from substance / medication-induced anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0571] Substance / medication-induced anxiety disorders are also associated with sleep disturbances: patients have difficulty falling asleep or frequently wake up during the night.

[0572] The severity of substance / medication-induced anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale, which can also be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0573] Sleep disturbances in substance / medication-induced anxiety disorders can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0574] Functional magnetic resonance imaging in individuals suffering from substance / medication-induced anxiety disorders reveals modulations of functional connectivity within and / or between resting-state networks involved in anxiety.

[0575] Treatment of patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of substance / drug-induced anxiety disorder, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the substance / drug-induced anxiety disorder.

[0576] The reduction or elimination of sleep disturbances in patients suffering from substance / drug-induced anxiety disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0577] The reduction or elimination of sleep disturbances in patients suffering from substance / drug-induced anxiety disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from substance / drug-induced anxiety disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0578] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from a substance / medication-induced anxiety disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0579] Improvement in sleep disturbance in patients with substance / medication-induced anxiety disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0580] Improvement in sleep disturbance in patients with substance / drug-induced anxiety disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with substance / drug-induced anxiety disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0581] In one embodiment, improvement in sleep disturbance in patients with substance / medication-induced anxiety disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0582] Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] The reduction or elimination of sleep disturbances in patients suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] In one embodiment, a reduction or elimination of sleep disturbances in patients with substance / medication-induced anxiety disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0585] As mentioned above, sleep disorder is a serious complaint of patients with substance / drug-induced anxiety disorder.Therefore, the improvement of sleep disorder also leads to the improvement of substance / drug-induced anxiety disorder.Because sleep disorder also affects other aspects of substance / drug-induced anxiety disorder, the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of substance / drug-induced anxiety disorder.

[0586] Improvement in substance / medication-induced anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0587] Improvement in substance / drug-induced anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in substance / drug-induced anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0588] In one embodiment, improvement in substance / medication-induced anxiety disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0589] somatic symptom disorder Somatic symptom disorder is a mental disorder diagnosed when a person has a significant focus on physical symptoms, such as pain, weakness, or shortness of breath, to the point that they cause significant distress and / or impairment and / or disruption to daily life. Illness-related emotions and behaviors are excessive or disproportionate.

[0590] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorders, the impairment is significant and, if persistent, can lead to chronic illness.

[0591] Patients with somatic symptom disorder may report sleep disturbances (ie, insomnia, patient discomfort with the quality, timing, and quantity of sleep), with resulting daytime distress and impairment.

[0592] Sleep disorders have the potential to create a real vicious cycle between physical symptoms and sleep disturbance.

[0593] For example, insomnia correlates with the presence of physical symptoms, and the severity of insomnia correlates with the severity of physical symptoms. However, this effect is not limited to insomnia, as alterations in the sleep-wake cycle may themselves be associated with the development of physical symptoms.

[0594] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptoms - Adult Scale. This scale includes 15 somatic symptoms. Respondents are asked to rate the severity of their personal somatic symptoms over the past seven days. Sleep disturbances are analyzed by scoring "Feeling tired or low on energy" and "Having trouble sleeping." Scores range from "0" ("not bothered at all") to "1" ("slightly bothered") to "2" ("very bothered"). Total scores can range from 0 to 30, with higher scores indicating greater somatic symptom severity. Cutoff scores of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0595] Additionally, sleep disturbances in individuals suffering from somatic symptom disorder can be assessed using the Pittsburgh Sleep Quality Index.

[0596] Brain functional connectivity analyses reveal modulations within and / or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Modulations are identified within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor network. Somatic symptom disorder may be associated with modulations in sensory-discriminative processing of somatic symptoms, which is influenced by emotional processing.

[0597] Treatment of patients suffering from somatic symptom disorder and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement in the somatic symptom disorder.

[0598] The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0599] The reduction or elimination of sleep disturbances in patients with somatic symptom disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with somatic symptom disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from somatic symptom disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0601] Improvement in sleep disturbance in patients suffering from somatic symptom disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] Improvement in sleep disturbance in patients with somatic symptom disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with somatic symptom disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] In one embodiment, improvement in sleep disturbance in patients with somatic symptom disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0604] Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0605] The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0606] In one embodiment, a reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0607] As mentioned above, sleep disturbances are common in patients with somatic symptom disorder. Therefore, improving sleep disturbances also leads to improvement of somatic symptom disorder. Because sleep disturbances also affect other aspects of somatic symptom disorder, the inventors conclude that improving sleep disturbances, particularly reducing or eliminating sleep loss, further contributes to the overall improvement of somatic symptom disorder.

[0608] Improvement in somatic symptom symptoms in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0609] Improvement in somatic symptom symptoms in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in somatic symptom symptoms in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] In one embodiment, improvement in somatic symptom symptoms in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0611] Obsessive-compulsive disorder and related disorders Obsessive-compulsive disorder (OCD) is a mental illness that causes unwanted recurring thoughts or sensations (obsessions) or urges to do something repeatedly (compulsions). Patients may suffer from both obsessions and compulsions.

[0612] Patients suffering from OCD may suffer from a treatment-resistant form of the disorder.

[0613] Sleep disturbances are a common feature in patients with OCD, and there is a correlation between the presence of sleep disturbances and the severity of OCD.

[0614] Sleep disturbances are associated with treatment resistance in OCD, and addressing the symptom as such leads to improved treatment efficacy.

[0615] Neuroimaging studies using functional magnetic resonance imaging in patients with OCD have shown altered functional connectivity within and / or between the frontoparietal, salience, and default mode networks. Altered functional connectivity in affected networks, particularly the default mode network, has also been associated with sleep disturbances.

[0616] Treating patients suffering from OCD, including treatment-resistant forms of OCD, and related sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the OCD.

[0617] The reduction or elimination of sleep disturbances in a patient suffering from OCD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] The reduction or elimination of sleep disturbances in patients with OCD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with OCD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from OCD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0620] Improvement in sleep disturbance in patients with OCD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0621] The improvement in sleep disturbance in patients with OCD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with OCD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] In one embodiment, improvement in sleep disturbance in patients with OCD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0623] Reduction or elimination of sleep disturbances in patients with OCD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0624] The reduction or elimination of sleep disturbances in patients with OCD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with OCD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0625] In one embodiment, a reduction or elimination of sleep disturbances in a patient with OCD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0626] As mentioned above, sleep disorder is common in patients with OCD.Therefore, improving sleep disorder also leads to the improvement of OCD.Because sleep disorder also affects other aspects of OCD, the inventors conclude that improving sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of OCD.

[0627] Improvement in OCD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] Improvement in OCD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in OCD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] In one embodiment, improvement in OCD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0630] Patients with body dysmorphic disorder (BDD) falsely perceive their appearance as flawed, which interferes with their ability to function in daily life and is accompanied by anxiety-provoking beliefs, ritualistic behaviors, and psychological distress.

[0631] Patients suffering from BDD may suffer from a treatment-resistant form of the disorder.

[0632] Sleep disturbances, particularly insomnia, are a common feature in patients with BDD and are associated with more severe psychopathology. Patients with BDD and sleep disturbances have higher self-reported BDD symptom severity, more depressive symptoms, and more impairment in daily activities.

[0633] Functional magnetic resonance imaging in patients with BDD reveals modulation within and / or between certain brain regions located in the default mode network, dorsal attention network, and salience network. Modulation of functional connectivity in affected networks, particularly in the default mode network, has also been associated with sleep disturbances.

[0634] Treating patients suffering from BDD and associated sleep disorders, including treatment-resistant forms of BDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, leading to improvement in BDD.

[0635] The reduction or elimination of sleep disturbances in a patient with BDD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0636] The reduction or elimination of sleep disturbances in a patient suffering from BDD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from BDD preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0637] In one embodiment, the reduction or elimination of sleep disturbances in a patient with BDD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0638] Improvement in sleep disturbance in patients with BDD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0639] Improvement in sleep disturbance in patients with BDD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with BDD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0640] In one embodiment, improvement in sleep disturbance in patients with BDD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0641] Reduction or elimination of sleep disturbances in patients with BDD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] The reduction or elimination of sleep disturbances in patients with BDD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with BDD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] In one embodiment, a reduction or elimination of sleep disturbances in a patient with BDD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0644] As mentioned above, sleep disorder is common in patients with BDD.Therefore, improving sleep disorder also leads to the improvement of BDD.Sleep disorder also affects other aspects of BDD, so the inventors conclude that improving sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of BDD.

[0645] Improvement in BDD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] Improvement in BDD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BDD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] In one embodiment, improvement in BDD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0648] Post-traumatic stress disorder (PTSD) Post-traumatic stress disorder (PTSD) is a mental health condition that can develop based on a frightening event that a patient has experienced or witnessed. Symptoms can include flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.

[0649] Patients suffering from PTSD may suffer from a treatment-resistant form of the disorder.

[0650] Sleep disturbances are associated with PTSD, with an estimated 70–90% of patients reporting at least one type of sleep disorder (insomnia, difficulty falling or staying asleep, or parasomnias such as nightmares).

[0651] Sleep disturbance in the form of difficulty falling asleep, difficulty staying asleep, or restless sleep is one of six features of altered arousal, at least two of which are required for a diagnosis of PTSD according to DSM-5 criteria.

[0652] Sleep disturbances in PTSD can be assessed by self-administered questionnaires such as the PTSD Symptom Scale or the Trauma Screening Questionnaire (TSQ).

[0653] The self-report version of the PTSD Symptom Scale is a 17-item self-report questionnaire for assessing symptoms of post-traumatic stress disorder. Sleep disturbances are assessed in the form of the occurrence of unsettling dreams or nightmares or difficulty falling asleep or staying asleep. Respondents are asked to indicate how often they have experienced certain sleep difficulties over the past two weeks or another appropriate recall window using a Likert-type scale ranging from 0 (never or only once) to 3 (almost always or 5 or more times per week). A score of 13 or higher indicates probable PTSD.

[0654] In the Trauma Screening Questionnaire, sleep (bad dreams or difficulty falling or staying asleep) is analyzed by two of 10 items that must be answered yes or no. Six or more positive answers indicate a risk of having PTSD.

[0655] Analysis of resting-state functional magnetic resonance imaging in patients with PTSD reveals modulations within and / or between regions located in the default mode network and salience network.

[0656] Treatment of patients suffering from PTSD, including treatment-resistant forms of PTSD, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the PTSD.

[0657] The reduction or elimination of sleep disturbances in a patient suffering from PTSD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0658] The reduction or elimination of sleep disturbances in a patient suffering from PTSD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from PTSD preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from PTSD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0660] Improvement in sleep disturbance in patients with PTSD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0661] The improvement in sleep disturbance in patients with PTSD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with PTSD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0662] In one embodiment, improvement in sleep disturbance in patients with PTSD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0663] Reduction or elimination of sleep disturbances in patients suffering from PTSD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0664] The reduction or elimination of sleep disturbances in patients with PTSD, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with PTSD, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] In one embodiment, a reduction or elimination of sleep disturbances in patients with PTSD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0666] As mentioned above, sleep disorder is an important aspect of PTSD.Therefore, improving sleep disorder also leads to the improvement of PTSD.Sleep disorder also affects other aspects of PTSD, so the inventors conclude that improving sleep disorder, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of PTSD.

[0667] Improvement in PTSD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0668] Improvement in PTSD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PTSD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] In one embodiment, improvement in PTSD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0670] pain disorders Sleep disorders occur in patients suffering from pain and are associated with chronic pain.

[0671] Chronic pain, also called persistent pain, is pain of long duration that persists beyond the normal recovery period, despite medication or treatment, for example, after injury or surgery. Patients may suffer from chronic pain without any apparent cause, such as a history of injury or surgery.

[0672] The prevalence of insomnia, defined as dissatisfaction with sleep quantity or quality, difficulty initiating, maintaining, or early morning awakening, within chronic pain populations is estimated to be 24–32%, nearly double the prevalence within the general population.

[0673] When sleep disorders are defined using polysomnography, actigraphy, or self-reported metrics, prevalence estimates within chronic pain patients rise to 40–80%.

[0674] The relationship between sleep disorders and chronic pain is thought to be bidirectional, but insomnia may subsequently develop into an independent condition requiring direct targeted treatment. Other conditions associated with sleep disorders, such as depression and anxiety, are very common within the chronic pain population.

[0675] The relationship between sleep disturbance and chronic pain is also reflected by, for example, the Brief Pain Inventory-Short (BPI-sf), a nine-item self-administered questionnaire used to assess the severity of patient's pain and the impact of this pain on patient's daily function.One item of BPI-sf is sleep.The questionnaire covers the sleep disturbance caused by pain in the past 24 hours.Therefore, sleep disturbance is a relevant aspect of chronic pain.

[0676] Chronic pain patients exhibit brain alterations in brain function and structure. These changes are associated with the persistence of pain long after the initial pain input has disappeared. Resting-state functional magnetic resonance imaging reveals distinct regional alterations within and / or between the default mode network, somatomotor / sensorimotor network, and salience network.

[0677] Treatment of patients suffering from chronic pain and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement in the chronic pain.

[0678] The reduction or elimination of sleep disturbances in a patient suffering from chronic pain is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0679] The reduction or elimination of sleep disturbances in patients suffering from chronic pain occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from chronic pain preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0680] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from chronic pain is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0681] Improvement in sleep disturbance in patients suffering from chronic pain, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0682] The improvement in sleep disturbance in patients suffering from chronic pain, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients suffering from chronic pain, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0683] In one embodiment, improvement in sleep disturbance in patients suffering from chronic pain, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0684] Reduction or elimination of sleep disturbances in patients suffering from chronic pain is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] The reduction or elimination of sleep disturbances in patients suffering from chronic pain, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from chronic pain, as reflected by an improvement in PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0686] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from chronic pain, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0687] As mentioned above, sleep disorder is an important disease aspect in patients with chronic pain.Therefore, the improvement of sleep disorder also leads to the improvement of chronic pain.Because sleep disorder also affects other aspects of chronic pain, the inventors conclude that the improvement of sleep disorder, especially the reduction or elimination of sleep loss, will further contribute to the overall improvement of chronic pain.

[0688] Improvement in chronic pain in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] Improvement in chronic pain in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in chronic pain in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0690] In one embodiment, improvement in chronic pain in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0691] Fibromyalgia is a chronic disorder characterized by musculoskeletal pain that spreads throughout the body or across multiple sites, accompanied by fatigue, sleep disturbances, memory and mood problems. Patients may also experience muscle and joint stiffness, tenderness to the touch, numbness or tingling in the arms and legs, problems with concentration, clarity of thought and memory (sometimes called "fibro-fog"), sensitivity to light, noise, smells and temperature, or digestive problems such as bloating or constipation.

[0692] Research has shown that people with fibromyalgia have a heightened sensitivity to pain and feel pain that other people do not.

[0693] Sleep disturbances and fatigue are common symptoms of fibromyalgia. Insomnia, non-restorative sleep, and fatigue are commonly used as markers for diagnosing fibromyalgia. Patients with fibromyalgia may also suffer from restless legs syndrome.

[0694] Sleep disturbances in fibromyalgia can be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0695] There is a two-way relationship between fibromyalgia and sleep disorders: pain symptoms can prevent patients from getting enough rest, and lack of sleep can lower pain thresholds and exacerbate pain and tenderness sensations.

[0696] The interplay of pain, fatigue, and poor sleep quality often interferes with a patient's ability to function at home or at work.

[0697] Current treatments for fibromyalgia are symptomatic.

[0698] Brain imaging and other studies have revealed evidence of altered signaling in the neural pathways that transmit and receive pain in people with fibromyalgia. These changes may also contribute to the fatigue, sleep disturbances, and cognitive problems experienced by many with the disorder.

[0699] Resting-state functional magnetic resonance imaging in patients with fibromyalgia shows modulation of functional connectivity within and / or between the DMN and the executive attention network, and between the DMN and the insular cortex, a brain region known to process evoked pain.

[0700] Treatment of patients suffering from fibromyalgia and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of fibromyalgia.

[0701] The reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia is observed on the 1st day, e.g., about 24 hours; the 7th day; the 14th day; and / or the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0702] The reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0703] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0704] Improvement in sleep disturbance in patients with fibromyalgia, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0705] The improvement in sleep disturbance in patients with fibromyalgia, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with fibromyalgia, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0706] In one embodiment, improvement in sleep disturbance in a patient with fibromyalgia, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0707] Reduction or elimination of sleep disturbances in patients with fibromyalgia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0708] The reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0709] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0710] As mentioned above, sleep disorder is one of the most common major complaints of patients with fibromyalgia.Therefore, improving sleep disorder also leads to the improvement of fibromyalgia.Because sleep disorder also affects other aspects of fibromyalgia, the inventors conclude that improving sleep disorder, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of fibromyalgia.

[0711] Improvement in fibromyalgia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] Improvement in fibromyalgia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in fibromyalgia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0713] In one embodiment, improvement in fibromyalgia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0714] Migraine is a headache that can cause severe throbbing pain or a pulsating sensation, usually on one side of the head. Migraine is often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last from a few hours to several days, and the pain can be so severe that it interferes with daytime activities.

[0715] Some patients experience symptoms known as auras before or along with the headache, which may include visual disturbances such as flashing lights or blind spots, tingling on one side of the face or in the arms or legs, and other disturbances such as difficulty speaking.

[0716] The most common sleep disturbance in patients with migraine is insomnia, which includes difficulty falling asleep or staying asleep, early morning awakenings, and unrefreshing sleep. Insomnia impairs daytime functioning, resulting in fatigue, decreased attention and concentration, and loss of motivation.

[0717] The presence of sleep disorders is associated with more frequent and severe migraines.

[0718] The Pittsburgh Sleep Quality Index (PSQI) is a common self-reported sleep quality questionnaire used to assess sleep quality over the past month and has been used in many studies to assess poor sleep quality in migraineurs.

[0719] Headache disorders are associated with atypical functional connectivity of regions involved in pain processing, as well as atypical functional connectivity within and / or between multiple core resting-state networks, including the salience and default mode networks.

[0720] Resting-state network analyses show differences in patients suffering from migraine compared to healthy controls. Studies during a migraine attack reveal significant abnormalities in networks associated with mediating the cognitive, attentional, somatosensory, and affective components of pain.

[0721] Treatment of patients suffering from migraine and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the migraine headaches.

[0722] The reduction or elimination of sleep disturbances in a patient suffering from migraine is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0723] The reduction or elimination of sleep disturbances in a patient suffering from migraine occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from migraine preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0724] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from migraine is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0725] Improvement in sleep disturbance in patients suffering from migraine, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0726] The improvement in sleep disturbance in a patient suffering from migraine, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in a patient suffering from migraine, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0727] In one embodiment, improvement in sleep disturbance in patients suffering from migraine, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0728] Reduction or elimination of sleep disturbances in patients suffering from migraine is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0729] The reduction or elimination of sleep disturbances in a patient suffering from migraine, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from migraine, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0730] As mentioned above, sleep disorder is one of the most common complaints of migraine sufferers.Therefore, improving sleep disorder also leads to the improvement of migraine.Because sleep disorder also affects other aspects of migraine, the inventors conclude that improving sleep disorder, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of migraine.

[0731] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from migraine, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0732] In patients who also suffer from an associated sleep disorder, improvement in migraine headache, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0733] Improvement in migraine headaches in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in migraine headaches in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0734] In one embodiment, improvement in migraine headaches in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0735] Mental and behavioral disorders due to the use of psychoactive substances Sleep disorders occur in patients suffering from certain mental and behavioral disorders due to the use of psychoactive substances.

[0736] Substance use disorder (SUD) is a mental disorder that affects a person's behavior and causes them to lose control over their use of substances, such as legal or illegal drugs, alcohol, or medication. Symptoms can range from moderate to severe, but the most severe form of SUD is addiction.

[0737] Resting-state functional connectivity (rsFC) has been found to be altered not only in patients with sleep disorders but also in patients with substance use disorders. In particular, deficits in cognitive control are associated with altered connectivity within and / or between resting-state networks, such as the default mode network, salience network, central executive network, limbic network, and reward network.

[0738] Substance / medication-related sleep disorders are characterized by alterations in sleep patterns severe enough to warrant independent clinical attention and are judged to be caused primarily by the pharmacological effects of a substance (i.e., a drug of abuse, medication, or toxin exposure).

[0739] Sleep disorders may be the result of intoxication with and / or withdrawal from substances such as alcohol, caffeine, cannabis, opioids, sedatives (hypnotics or anxiolytics), tobacco, stimulants (such as cocaine), or other substances.

[0740] Certain medications, such as adrenergic agonists / antagonists, dopamine agonists / antagonists, cholinergic agonists / antagonists, serotonergic agonists / antagonists, antihistamines, or corticosteroids, may also cause sleep disturbances.

[0741] Depending on the substance involved, one of four types of sleep disorder has been reported: insomnia and daytime sleepiness are the most common, while parasomnia is less common. A mixed type is observed when more than one type of sleep disorder-related symptom is present, none of which predominates.

[0742] Because some substance withdrawal states can be prolonged, sleep disorders may develop as early as 4 weeks after cessation of substance use, and the disorder may have atypical characteristics (e.g., atypical age of onset or course) relative to other sleep disorders.

[0743] The significant impact of sleep disturbances in substance use disorders has been reflected by the development of specialized sleep questionnaires, such as the Substance Use Sleep Scale (SUSS). The SUSS questionnaire consists of 23 questions and two domains: "mental and physical sleep problems" and "substance-related sleep problems." Scoring ranges from 0 to 23, with lower scores indicating better sleep and higher scores indicating more poor sleep.

[0744] Treatment of patients suffering from substance use disorders and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the substance use disorder.

[0745] The reduction or elimination of sleep disturbances in a patient suffering from a substance use disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0746] The reduction or elimination of sleep disturbances in patients with substance use disorders occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients with substance use disorders preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0747] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from a substance use disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0748] Improvement in sleep disturbance in patients with substance use disorders, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0749] The improvement in sleep disturbance in patients with substance use disorders, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in patients with substance use disorders, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0750] In one embodiment, improvement in sleep disturbance in patients with a substance use disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0751] Reduction or elimination of sleep disturbances in patients with substance use disorders is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0752] The reduction or elimination of sleep disturbances in patients suffering from a substance use disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from a substance use disorder, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0753] In one embodiment, reduction or elimination of sleep disturbances in patients with a substance use disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0754] As mentioned above, sleep disorder is an important disease aspect in patients with substance use disorder.Therefore, improving sleep disorder also leads to improving substance use disorder.Because sleep disorder also affects other aspects of substance use disorder, the inventors conclude that improving sleep disorder, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of substance use disorder.

[0755] Improvement in substance use disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0756] Improvement in substance use disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in substance use disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0757] In one embodiment, improvement in substance use disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0758] Psychotic disorders Psychotic disorders are severe mental disorders that cause abnormal thinking and perceptions. Psychotic disorders are characterized by significant impairments in reality testing and altered behavior, and are manifested by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking (typically manifested as incoherent speech), markedly disorganized behavior, and experiences of passivity and control, and negative symptoms such as flat or blunted affect and apathy, and psychomotor impairments.

[0759] Patients suffering from a psychotic disorder may suffer from a treatment-resistant form of the disorder.

[0760] Insomnia and nightmare disorder are the most common sleep disorders associated with psychotic disorders, but sleep-related hallucinations, excessive sleepiness disorder, restless legs syndrome, periodic limb movement disorder, teeth grinding, sleep paralysis, night terrors, or circadian rhythm disorders may also be seen as comorbidities.In many cases, patients suffer from multiple disorders rather than just one single sleep disorder.Most sleep disorders are rated as severe in terms of chronicity, frequency, and distress or impairment.

[0761] Due to the significant impact that sleep disturbances have on the course of psychotic disorders, the sleep quality of patients suffering from psychotic disorders is assessed by rating scales commonly used to diagnose or evaluate sleep disorders, such as the PSQI or Sleep50.

[0762] Functional magnetic resonance imaging of resting-state brain networks in patients with psychosis reveals significant modulations in distinct regions within and / or between the central executive, default mode, and salience networks. Modulations in resting-state networks can also be identified in patient populations at risk for psychosis.

[0763] Treatment of patients suffering from psychotic disorders, including treatment-resistant forms of psychotic disorders, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of the psychotic disorder.

[0764] The reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0765] The reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0766] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0767] Improvement in sleep disturbances in patients with a psychotic disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0768] The improvement in sleep disturbance in a patient suffering from a psychotic disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in a patient suffering from a psychotic disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0769] In one embodiment, improvement in sleep disturbance in a patient suffering from a psychotic disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0770] Reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period spans from the time the acute hallucinogenic high experience abated after the last administration to the time of assessment.

[0771] The reduction or elimination of sleep disturbances in patients suffering from a psychotic disorder, as reflected by an improvement in PSQI total score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period extends from the time the acute hallucinogenic high experience subsides after the last administration to the time of assessment. The reduction or elimination of sleep disturbances in patients suffering from a psychotic disorder, as reflected by an improvement in PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0772] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from a psychotic disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0773] As mentioned above, the occurrence of various forms of sleep disorder is an important disease aspect in patients with psychotic disorder.Therefore, the improvement of sleep disorder is also connected to the improvement of psychotic disorder.Because sleep disorder also affects other aspects of psychotic disorder, the inventors conclude that the improvement of sleep disorder will further contribute to the overall improvement of psychotic disorder.

[0774] Improvement in the psychotic disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0775] Improvement of the psychotic disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of the psychotic disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0776] In one embodiment, improvement in a psychotic disorder in a patient who also suffers from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0777] Schizophrenia is a severe mental health condition characterized by disturbances in multiple mental modalities, including thought, perception, self-experience, cognition, volition, emotion, and behavior. Psychomotor disturbances, including catatonia, may be present.

[0778] Patients suffering from schizophrenia may suffer from a treatment-resistant form of the disorder.

[0779] In individuals with schizophrenia, abnormal resting-state functional connectivity has been reported, particularly within and / or between the default mode network, frontoparietal network, and salience network.In individuals at high risk for psychosis and those diagnosed with schizophrenia, several studies have found an association between sleep disturbances and symptom severity.

[0780] Psychotic experiences often interfere with the ability to sleep well, and the resulting sleep problems lead to daytime fatigue, thus impairing the ability of people with schizophrenia to cope with their psychotic symptoms.

[0781] Insomnia is the sleep disorder most strongly associated with schizophrenia.

[0782] Patients with schizophrenia and coexisting sleep disorders tend to have a poorer quality of life as assessed by physical health, mental health, social relationships, and environmental factors. Schizophrenia patients with sleep disorders also report significantly lower satisfaction with life, and the presence of insomnia and comorbid nightmares in these patients is associated with an increased risk of suicide attempts.

[0783] Sleep disturbances are an essential aspect of patients suffering from schizophrenia and can be assessed by common sleep scales such as the Pittsburgh Sleep Quality Index (PSQI).

[0784] Treatment of patients suffering from schizophrenia, including treatment-resistant forms of schizophrenia, and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which leads to improvement of schizophrenia.

[0785] The reduction or elimination of sleep disturbances in a patient suffering from schizophrenia is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0786] The reduction or elimination of sleep disturbances in a patient suffering from schizophrenia occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from schizophrenia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0787] In one embodiment, the reduction or elimination of sleep disturbances in a patient suffering from schizophrenia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0788] Improvement in sleep disturbance in patients with schizophrenia, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0789] The improvement in sleep disturbance in a patient suffering from schizophrenia, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in sleep disturbance in a patient suffering from schizophrenia, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0790] In one embodiment, improvement in sleep disturbance in a patient with schizophrenia, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0791] Reduction or elimination of sleep disturbances in a patient suffering from schizophrenia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0792] The reduction or elimination of sleep disturbances in a patient suffering from schizophrenia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from schizophrenia, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0793] In one embodiment, a reduction or elimination of sleep disturbances in a patient suffering from schizophrenia, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0794] As mentioned above, sleep disorder is central to the clinical picture of schizophrenia.Therefore, improving sleep disorder also leads to the improvement of schizophrenia.Because sleep disorder also affects other aspects of schizophrenia, the inventors conclude that improving sleep disorder will further contribute to the overall improvement of schizophrenia.

[0795] Improvement in schizophrenia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0796] Improvement in schizophrenia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in schizophrenia in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0797] In one embodiment, improvement in schizophrenia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0798] Huntington's disease Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary choreiform movements. HD is associated with cognitive and behavioral impairments. Indeed, progressive cognitive impairment is a core feature of HD, accompanied by early changes in executive function (i.e., processing speed, organization, and planning). Cognitive and related behavioral changes often precede the appearance of typical motor abnormalities.

[0799] Other common symptoms of HD are circadian rhythm and sleep abnormalities, which can be observed from the earliest stages of the disease or even before the onset of clinical symptoms. Up to 90% of patients report sleep problems, with more than half rating these as severe. Studies have demonstrated that some sleep disorders are found in the very early stages of HD and even in mutation carriers at premorbid stages.

[0800] The most common sleep problems reported by HD patients include insomnia, difficulty falling asleep, frequent nighttime awakenings, and excessive daytime sleepiness, and specific alterations in sleep architecture have been identified in HD.

[0801] Sleep disturbances in Huntington's disease can be assessed using a detailed self-report questionnaire designed to assess sleep problems specific to HD patients (Goodman et al. Identifying sleep disturbances in Huntington's disease using a simple disease-focused questionnaire. PLoS Curr. 2010 Oct 15;2:RRN1189). This questionnaire contains 45 questions grouped into four subcategories: sleep quality (e.g., difficulty falling asleep or staying asleep), motor activity (e.g., painful muscle cramps in the arms or legs that awaken the patient during the night), abnormal nighttime behavior (e.g., acting out dreams, injuring self or others while dreaming), and other aspects of sleep disturbance (e.g., nocturia, numbness, paresthesia, sleep apnea, and daytime somnolence).

[0802] Additionally, assessment of sleep disturbances can be by the Pittsburgh Sleep Quality Index (PSQI).

[0803] In HD, the functional connectivity structure at rest is significantly altered. Resting-state networks that serve sensory-motor and cognitive functions are involved in the pathophysiological mechanisms of HD. HD shows early and widespread disruption of large-scale cognitive networks, which are associated with cognitive and disease burden scores. The default mode network is affected. For example, manifest HD shows modulation of the functional connectivity of key brain regions of the DMN (i.e., the ventromedial prefrontal cortex and angular gyrus).

[0804] Treatment of patients suffering from HD and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, leading to improvement of HD.

[0805] The reduction or elimination of sleep disturbances in a patient with HD is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0806] The reduction or elimination of sleep disturbances in a patient suffering from HD occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from HD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0807] In one embodiment, the reduction or elimination of sleep disturbances in a patient with HD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0808] Improvement in sleep disturbance in patients with HD, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0809] Improvement in sleep disturbance in patients with HD, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients with HD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0810] In one embodiment, improvement in sleep disturbance in patients with HD, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0811] Reduction or elimination of sleep disturbances in patients with HD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a reduction to 5 or less, on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0812] The reduction or elimination of sleep disturbances in a patient with HD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient with HD, as reflected by an improvement in the PSQI total score, particularly a decrease to 5 or less, preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0813] In one embodiment, a reduction or elimination of sleep disturbances in a patient with HD, as reflected by an improvement in PSQI score, particularly a reduction to 5 or less, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0814] As mentioned above, sleep disorder is one of the most common major complaints of patients with HD.Therefore, improving sleep disorder will also lead to the improvement of HD.Because sleep disorder also affects other aspects of HD, the inventors conclude that improving sleep disorder, especially reducing or eliminating sleep loss, will further contribute to the overall improvement of HD.

[0815] Improvement in HD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0816] Improvement in HD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in HD in patients who also suffer from an associated sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0817] In one embodiment, improvement in HD in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S score, is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0818] Parkinson's disease (PD) Parkinson's disease (PD) is a condition characterized by slowly progressive problems with movement, most commonly involving slowness of movement, resting tremor, and gait unsteadiness that can lead to falls.

[0819] Sleep disturbances occur frequently in PD and can cause as much or more discomfort as motor symptoms, substantially reducing the quality of life of patients and caregivers.

[0820] The most common sleep disorders in PD are insomnia, sleep-disordered breathing, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related movement disorders such as restless legs syndrome.

[0821] Sleep in patients with Parkinson's disease can be assessed by scales developed specifically for this patient population, such as the Unified Parkinson's Disease Rating Scale-Movement Disorder Society (UPDRS-MDS), the Parkinson's Disease Sleep Scale-2 (PDSS-2), and also by the Pittsburgh Sleep Questionnaire.

[0822] The Unified Parkinson's Disease Rating Scale-Movement Disorder Society (UPDRS-MDS) consists of four parts that take into account non-motor experiences of daily living, motor experiences of daily living, motor test...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof for use in the treatment of a patient suffering from a sleep disorder, wherein said 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via an intravenous, intramuscular or subcutaneous route.

2. 2. The method of claim 1, wherein the sleep disorder is insomnia.

3. 2. The method of claim 1, wherein the sleep disorder is hypersomnia.

4. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the sleep disorder is a circadian rhythm disorder.

5. 2. The method of claim 1, wherein the sleep disorder is a parasomnia.

6. 2. The method of claim 1, wherein the sleep disorder is a sleep-related breathing disorder.

7. 2. The method of claim 1, wherein the sleep disorder is a sleep-related movement disorder.

8. 8. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 7, wherein the sleep disorder is an idiopathic sleep disorder.

9. 2. The method of claim 1, wherein the patient is suffering from a psychiatric or nervous system disorder associated with said sleep disorder.

10. 10. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 9, wherein the patient suffering from a psychiatric or neurological disorder is suffering from a treatment-resistant form of said disorder.

11. 2. The method of claim 1, wherein the patient is suffering from a disorder characterized by depressive episodes associated with said sleep disorder.

12. 12. The method of claim 11, wherein the patient suffering from a disorder characterized by depressive episodes suffers from a treatment-resistant form of the disorder.

13. 2. The method of claim 1, wherein the patient is suffering from major depressive disorder (MDD) associated with the sleep disorder.

14. 14. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 13, wherein the patient suffering from MDD is suffering from a treatment-resistant form of the disorder.

15. 2. The method of claim 1, wherein the patient is suffering from postpartum depression (PPD) associated with the sleep disorder.

16. 16. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 15, wherein the patient suffering from PPD is suffering from a treatment-resistant form of the disorder.

17. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 15 or 16, wherein the patient further suffers from maternal dysfunction.

18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 17, wherein the patient has a Birkin Index of Maternal Function (BIMF) score of 80 or less, such as 65 or less.

19. 19. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 17 or 18, wherein the treatment improves maternal function.

20. 20. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 19, wherein said improvement in maternal function is reflected by an improvement in said BIMF total score of 10% or more, preferably 20% or more.

21. 21. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 19 or 20, wherein the improvement in maternal function is reflected by at least an improvement in the BIMF total score at 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

22. 21. The method of claim 19 or 20, wherein the improvement in maternal functioning, as reflected by at least an improvement in the BIMF sum score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and wherein the improvement in maternal functioning, as reflected by at least an improvement in the BIMF sum score, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

23. 2. The method of claim 1, wherein the patient suffers from a bipolar disorder associated with the sleep disorder.

24. 24. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 23, wherein the patient is suffering from bipolar II disorder associated with the sleep disorder.

25. 24. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 23, wherein the patient is suffering from bipolar I disorder associated with the sleep disorder.

26. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 23 to 25, wherein the patient is currently suffering from a major depressive episode.

27. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 23 to 26, wherein the patient suffering from bipolar disorder is suffering from a treatment-resistant form of the disorder.

28. 2. The method of claim 1, wherein the patient suffers from seasonal affective disorder associated with the sleep disorder.

29. 29. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 28, wherein the patient suffering from seasonal affective disorder is suffering from a treatment-resistant form of the disorder.

30. 2. The method of claim 1, wherein the patient suffers from a persistent depressive disorder associated with the sleep disorder.

31. 31. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 30, wherein the patient suffering from persistent depressive disorder is suffering from a treatment-resistant form of the disorder.

32. 2. The method of claim 1, wherein the patient is suffering from an anxiety disorder associated with the sleep disorder.

33. 33. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 32, wherein the patient suffering from an anxiety disorder is suffering from a treatment-resistant form of the disorder.

34. 2. The method of claim 1, wherein the patient suffers from separation anxiety disorder associated with the sleep disorder.

35. 35. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 34, wherein the patient suffering from separation anxiety disorder is suffering from a treatment-resistant form of the disorder.

36. 2. The method of claim 1, wherein the patient is suffering from agoraphobia associated with said sleep disorder.

37. 37. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 36, wherein the patient suffering from agoraphobia is suffering from a treatment-resistant form of the disorder.

38. 2. The method of claim 1, wherein the patient suffers from generalized anxiety disorder (GAD) associated with the sleep disorder.

39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 38, wherein the patient suffering from GAD is suffering from a treatment-resistant form of the disorder.

40. 2. The method of claim 1, wherein the patient suffers from social anxiety disorder (SAD) associated with the sleep disorder.

41. 41. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 40, wherein the patient suffering from SAD suffers from a treatment-resistant form of the disorder.

42. 2. The method of claim 1, wherein the patient suffers from a panic disorder associated with the sleep disorder.

43. 43. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 42, wherein the patient suffering from a panic disorder is suffering from a treatment-resistant form of the disorder.

44. 2. The method of claim 1, wherein the patient suffers from a phobia associated with the sleep disorder.

45. 45. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 44, wherein the patient suffering from a phobia suffers from a treatment-resistant form of the disorder.

46. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from a substance / medication-induced anxiety disorder associated with said sleep disorder.

47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 46, wherein the patient suffering from a substance / medication-induced anxiety disorder is suffering from a treatment-resistant form of the disorder.

48. 2. The method of claim 1, wherein the patient is suffering from somatic symptoms associated with the sleep disorder.

49. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 48, wherein the patient suffering from somatic symptom disorder is suffering from a treatment-resistant form of the disorder.

50. 2. The method of claim 1, wherein the patient suffers from obsessive-compulsive disorder or an associated disorder associated with the sleep disorder.

51. 51. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 50, wherein the obsessive-compulsive disorder or related disorder is obsessive-compulsive disorder (OCD).

52. 52.

52.

52.

52.

52.

52.

52. The method of claim 50, wherein the patient is suffering from a treatment-resistant form of the disorder.

53. 2. The method of claim 1, wherein the patient suffers from body dysmorphic disorder (BDD) associated with said sleep disorder.

54. 54. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 53, wherein the patient suffering from BDD suffers from a treatment-resistant form of the disorder.

55. 2. The method of claim 1, wherein the patient is suffering from post-traumatic stress disorder (PTSD) associated with the sleep disorder.

56. 56. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 55, wherein the patient suffering from PTSD is suffering from a treatment-resistant form of the disorder.

57. 2. The method of claim 1, wherein the patient is suffering from a pain disorder associated with the sleep disorder.

58. 58. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 57, wherein the patient is suffering from chronic pain associated with the sleep disorder.

59. 59. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 57 or 58, wherein the patient is suffering from a treatment-resistant form of the disorder.

60. 2. The method of claim 1, wherein the patient suffers from fibromyalgia associated with a sleep disorder.

61. 2. The method of claim 1, wherein the patient is suffering from migraine headaches associated with a sleep disorder.

62. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from a mental and behavioral disorder due to the use of psychoactive substances associated with said sleep disorder.

63. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 62, wherein the patient is suffering from a substance use disorder (SUD) associated with the sleep disorder.

64. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 62 or 63, wherein the patient is suffering from a treatment-resistant form of the disorder.

65. 2. The method of claim 1, wherein the patient is suffering from a psychotic disorder associated with said sleep disorder.

66. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 65, wherein the patient suffering from a psychotic disorder is suffering from a treatment-resistant form of the disorder.

67. 2. The method of claim 1, wherein the patient is suffering from schizophrenia associated with the sleep disorder.

68. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 67, wherein the patient suffering from schizophrenia is suffering from a treatment-resistant form of the disorder.

69. 2. The method of claim 1, wherein the patient is suffering from Huntington's disease associated with said sleep disorder.

70. 2. The method of claim 1, wherein the patient is suffering from Parkinson's disease associated with a sleep disorder.

71. 2. The method of claim 1, wherein the patient is suffering from dementia associated with a sleep disorder.

72. 2. The method of claim 1, wherein the patient suffers from Alzheimer's dementia associated with the sleep disorder.

73. 2. The method of claim 1, wherein the patient is suffering from Parkinson's disease dementia associated with the sleep disorder.

74. 2. The method of claim 1, wherein the patient is suffering from dementia with Lewy bodies associated with the sleep disorder.

75. 2. The method of claim 1, wherein the patient is suffering from vascular dementia associated with the sleep disorder.

76. 2. The method of claim 1, wherein the patient is suffering from frontotemporal dementia associated with a sleep disorder.

77. 2. The method of claim 1, wherein the patient suffers from an eating disorder associated with the sleep disorder.

78. 78. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 77, wherein the patient suffering from an eating disorder is suffering from a treatment-resistant form of the disorder.

79. 2. The method of claim 1, wherein the patient suffers from attention deficit hyperactivity disorder (ADHD) associated with the sleep disorder.

80. 80. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 79, wherein the patient suffering from ADHD is suffering from a treatment-resistant form of the disorder.

81. 2. The method of claim 1, wherein the patient suffers from a personality disorder associated with the sleep disorder.

82. 82. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 81, wherein the patient is suffering from a schizotypal personality disorder associated with the sleep disorder.

83. 83. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 81 or 82, wherein the patient is suffering from a treatment-resistant form of the disorder.

84. 2. The method of claim 1, wherein the patient suffers from borderline personality disorder (BPD) associated with the sleep disorder.

85. 85. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 84, wherein the patient suffering from BPD is suffering from a treatment-resistant form of the disorder.

86. 2. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from an autism spectrum disorder (ASD) associated with the sleep disorder.

87. 2. The method of claim 1, wherein the patient suffers from chronic fatigue syndrome associated with the sleep disorder.

88. 88. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 87, wherein the patient suffering from chronic fatigue syndrome suffers from a treatment-resistant form of the disorder.

89. 2. The method of claim 1, wherein the sleep disorder is caused by traumatic brain injury.

90. 2. The method of claim 1, wherein the sleep disorder is caused by HIV infection.

91. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the sleep disorder is due to a post-COVID condition.

92. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 91, wherein said treatment reduces or eliminates said sleep disorder.

93. 93. The method of claim 92, wherein the reduction or elimination of sleep disturbance is observed 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

94. 93. The 5-MeO-DMT or pharma- ceutically acceptable salt thereof for use according to claim 92, wherein said reduction or elimination of sleep disturbance occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and said reduction or elimination of sleep disturbance persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

95. 93. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 92, wherein said reduction or elimination of sleep disturbance is observed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof and preferably persists for at least 14 days, more preferably for at least 28 days.

96. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 9 to 95, wherein said treatment leads to an improvement of said diagnosed disorder in patients who also suffer from a related sleep disorder.

97. 97. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 96, wherein the improvement in the diagnosed disorder in a patient who also suffers from an associated sleep disorder, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

98. 97. The method of claim 96, wherein the improvement of the diagnosed disorder in a patient who also suffers from a related sleep disorder, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and wherein the improvement of the diagnosed disorder in a patient who also suffers from a related sleep disorder, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof; in particular for at least 14 days; more preferably for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

99. 97. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 96, wherein the improvement in the diagnosed disorder in patients who also suffer from an associated sleep disorder, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores, is observed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and preferably persists for at least 14 days, more preferably for at least 28 days.

100. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 99, wherein the 5-MeO-DMT or a salt thereof is administered in a dose or dosing regimen that causes the patient to experience a hallucinogenic high experience.

101. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 100, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

102. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 100, wherein a dosage of about 2 mg; or about 5 mg; or about 8 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

103. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 100, wherein a dosage of about 1 mg; or about 2 mg; or about 3 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

104. 102. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 101, wherein the 5-MeO-DMT or a salt thereof is administered in a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration, unless the patient experiences a hallucinogenic high experience.

105. 105. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1-101, or 104, wherein the 5-MeO-DMT is administered at a dosage of about 1 mg to about 3 mg for a first administration, then increased to a dosage of about 4 mg to about 6 mg for a second administration unless the patient has already experienced a hallucinatory high experience, then increased to a dosage of about 7 mg to about 9 mg for a third administration unless the patient has already experienced a hallucinatory high experience, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

106. 106. The method of claim 105, wherein the first dose of 5-MeO-DMT is about 2 mg; the second dose of 5-MeO-DMT is about 5 mg; the third dose of 5-MeO-DMT is about 8 mg; or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

107. 105. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1-101, or 104, wherein the 5-MeO-DMT is administered at a dosage of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a hallucinogenic high experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a hallucinogenic high experience, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

108. 108. The method of claim 107, 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 an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

109. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 104 to 108, wherein the interval between two administrations is 1 hour or more and 24 hours or less, for example about 1 to 4 hours, preferably 1 to 2 hours.

110. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 100 to 109, wherein the onset of a hallucinatory peak experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Mystical Experiences Questionnaire-Revised (MEQ30), or by achieving at least 60% of the maximum possible score on the Oceanic Feeling (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experiences Scale (PES) total score of at least 75.

111. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 110, wherein the onset of a hallucinatory peak experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

112. 112. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1 to 111, wherein the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous injection.

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