5-MeO-DMT for use in the treatment of sleep disorders

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used in the treatment of patients with sleep disorders.

Description

[Technical Field]

[0001] The present invention relates to improved methods for treating sleep disorders, particularly sleep disorders in patients with psychiatric or neurological disorders, such as disorders characterized by depressive episodes, including, for example, major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), including bipolar disorder types I and II; anxiety disorders, including 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, including obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); These include post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia and migraine; mental and behavioural disorders due to the use of psychoactive substances, 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; and psychiatric or neurological disorders related to HIV, traumatic brain injury or the after-effects of COVID-19.

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

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

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

[0005] Sleep disorders not only have a serious impact on quality of life but can also lead to a variety of secondary health problems.

[0006] Therefore, there is a need for treatments for sleep disorders, particularly sleep disorders associated with psychiatric or neurological disorders. Summary of the Invention

[0007] In particular, it is an object of the present invention to provide a therapy that is more effective (i.e., a) a greater percentage of patients exhibiting 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) than previously described therapies.

[0008] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are associated with higher patient compliance rates (including higher rates of delayed ejaculation onset) than previously described therapies. A still further object of the present invention is to identify specific disease states and subgroups of specific disease states 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 with a sleep disorder, particularly insomnia, hypersomnia, and / or a circadian rhythm disorder.

[0010] The present invention also provides 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use in treating a patient with a parasomnia, a sleep-related breathing disorder, or a sleep-related movement disorder.

[0011] Sleep disorders may be episodic or may occur in patients with psychiatric or neurological disorders, such as disorders characterized by depressive episodes, including major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), including bipolar I and II; anxiety disorders, including 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, including obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTS) D); pain disorders, such as chronic pain, fibromyalgia and migraine; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); 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 neurological disorders related to HIV, traumatic brain injury or the after-effects of COVID-19.

[0012] The present invention also provides dose ranges and dosing regimens in certain embodiments useful for treating sleep disorders. DETAILED DESCRIPTION OF THE INVENTION

[0013] 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.

[0014] As used in the context of the present invention, a "patient" to be treated is a human subject who is identified by a licensed professional in accordance with accepted medical practice as having a sleep disorder, or who has been diagnosed by a licensed professional in accordance with accepted medical practice as having a psychiatric or neurological disorder associated with a sleep disorder, in which case evaluation of the sleep disorder may or may not be part of the diagnosis.

[0015] Diagnosis of psychiatric or neurological disorders can be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. Depending on the case, as will be apparent from the discussion of specific conditions below, the criteria can be modified or supplemented to better define patients or patient groups who will benefit from treatment according to the present invention. In either case, the diagnosis is made by a physician or psychologist. It is not sufficient for the human subject to consider themselves to have a disorder.

[0016] As used in the context of this invention, unless otherwise specified, 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 a disease or to eliminate a disease, condition, or disorder.

[0017] "Treatment of a sleep disorder" includes the management and care of a patient for the purpose of combating a disease, condition, or 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. Sleep disorders may be idiopathic or associated with psychiatric or neurological disorders.

[0018] Patient may have treatment-resistant disorder. Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses. In particular, patient does not show sufficient improvement after at least two appropriate treatment courses, at least one of which is drug therapy, for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses. At least two appropriate treatment courses are particularly administered in the current episode of disease, for example, in the current episode of depression, when patient has a disease characterized by depressive episodes.

[0019] 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 a researcher, physician, or other clinician desires, including alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0020] "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 neurological disorder or aspect of such a disorder.

[0021] The severity and change in severity of a condition can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and treatment effectiveness.

[0022] The CGI rating scale was developed to provide a brief, independent assessment from the clinician's perspective of a patient's overall functional status before and after treatment (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0023] 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.

[0024] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0025] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, clinicians compare 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 starting treatment: 1 = very much; 2 = very much; 3 = very minimal; 4 = unchanged from baseline (before treatment was started); 5 = very minimal; 6 = very much worse; 7 = very much worse since treatment was started."

[0026] 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).

[0027] In addition to the individual items of the scales described herein, subcombinations of the individual items can also be used to assess specific disease aspects.

[0028] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a predetermined amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered by nasal inhalation, by buccal administration, or by sublingual administration.

[0029] As used in the context of this invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosage regimen") shall mean the prescribed sequence of one or more individual administrations.

[0030] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and fine suspended solids and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of the active agent as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When the percentage of "degradation products" is described in the context of the present invention, it refers to the amount of degradation products of the active agent present in the sample divided by the amount of active agent present in the sample plus the amount of active agent degradation products present in the sample multiplied by 100%, i.e., (total amount of all active agent degradation products present in the sample) / ((amount of active agent present in the sample) + (total amount of all active agent degradation products present in the sample)) × 100%. As used herein, the term "impurities" refers to undesirable compounds contaminating a sample of an active agent. Impurities may be contained in the starting material prior to aerosol formation, or they may be degradation products.

[0031] The term "purity" refers to 100% minus the percentage of all active agent degradation products present plus all other impurities present, i.e., 100% - (the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) / (the amount of active agent present + the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0032] The term "mass median aerodynamic diameter" (MMAD) refers to the calculated diameter above which 50% of the particles present in an aerosol are larger and 50% are smaller. The term "aerosol particle mass concentration" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle generation rate" refers to the mass of aerosolized active agent per unit time of aerosolization.

[0033] Sleep disorders There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. NREM sleep can be divided into four stages. Each of these NREM stages corresponds to an increasing depth of sleep. NREM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, NREM sleep is deeper, taking up a disproportionate amount of time, especially in the first cycle of sleep. As the night progresses, NREM sleep becomes shallower, with a larger portion of each cycle being allocated to REM sleep.

[0034] Normal, healthy sleep consists of the different stages described above that progress sequentially during the night in a tightly regulated sequence.

[0035] Disruption of this tight regulation results in sleep disorders.

[0036] A sleep disorder is a condition that affects the quality, timing, or duration of sleep, whether it is sudden or occurs in association with a medical condition such as a psychiatric or neurological disorder. Sleep disorders affect the ability to function properly while awake.

[0037] Common forms of sleep disorders include disorders of falling asleep and maintaining sleep (insomnias), disorders of excessive sleepiness (hypersomnias), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disordered breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0038] Insomnia is a sleep disorder that causes difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep, frequent waking during the night and difficulty falling back asleep, waking too early in the morning, non-restorative sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, difficulty concentrating, or accidents at work or while driving.

[0039] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. Sleep drunkenness involves difficulty transitioning from sleep to wakefulness. Individuals with sleep drunkenness report confusion, disorientation, bradykinesia, and frequent falls back asleep.

[0040] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances caused by alterations in an individual's internal circadian rhythm or misalignment between an individual's circadian rhythm and the individual's desired or required work or social schedule. This desynchronization may be temporary or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep duration is typically short and fragmented, desired wakefulness performance is impaired, and temporary attempts to return to a normal sleep schedule are unsuccessful.

[0041] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (e.g., sleepwalking or nightmares) experienced before sleep onset, during sleep, or during periods of arousal between sleep and wakefulness. Their characteristics, severity, and frequency vary widely among individuals. Parasomnias can impair sleep quality.

[0042] 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 the 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 to control breathing, for example, due to an underlying medical condition. Central sleep apnea can have serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, leading to sleep fragmentation through micro-arousals, or awakenings. This can result in excessive daytime sleepiness.

[0043] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements interfere with sleep or its onset. The most common are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0044] Not getting the right amount or quality of sleep can lead to personality changes and may worsen existing mental illnesses or even precipitate the onset of new ones. Sleep disorders can also interfere with cognitive function and cause memory problems. Sleep-deprived people may experience difficulty making decisions, irritability, performance problems, and slowed reaction times. Sleep deprivation can also negatively impact quality of life by contributing to the development of obesity, diabetes, and heart disease.

[0045] Treatment for sleep disorders varies depending on the type of disorder and its underlying cause. Proper sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are considered first-line treatments. If this is ineffective, medication or psychological treatments may be used.

[0046] Available treatments do not work for all patients, may be associated with side effects, and / or may require long-term treatment to be effective.

[0047] In patients with sleep disorders associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorders do not always improve the sleep disorders.

[0048] For example, sleep disorders are often associated with psychiatric disorders such as depression.However, treating depression does not necessarily improve the associated sleep disorders.Many antidepressants have been proven to affect sleep structure, and while some classes of antidepressants improve sleep, some may cause sleep disorders.

[0049] Measurement of sleep disturbances Sleep can be assessed by measuring parameters such as sleep duration, sleep latency, and frequency and duration of awakenings throughout the night. Quantitative measures can be assessed using objective methods such as polysomnography, actigraphy, and sleep onset latency measurements, or by self-reported measures (questionnaires).

[0050] Polysomnography is a procedure that requires overnight monitoring of a patient in a specialized hospital, measuring a wide range of functions throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0051] Another quantitative measurement is actigraphy, which uses a worn actimetry sensor to measure motor activity and continuously record it to assess the sleep / wake cycle. This method allows patients to continue their normal routine while recording the necessary data in a natural sleep environment.

[0052] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective measure of how long it takes a person to fall asleep over multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal, while less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Analysis of the accompanying brain activity can aid in further diagnosis of sleep disorders.

[0053] Sleep assessment questionnaires assess elements of sleep quality, such as perceived depth of sleep, difficulty waking, and feeling refreshed after sleep, as well as other factors that may affect sleep quality, such as comorbid conditions and medication use. Assessing the qualitative aspects of the sleep experience is important because dissatisfaction with sleep often persists even when quantitative indicators of sleep are normal.

[0054] Questionnaires may be useful not only for rapid and accurate assessment of complex clinical problems but also for tracking patient progress.

[0055] Various sleep quality indices are known. The following indices include examples of questionnaires that assess overall sleep, as well as examples of questionnaires that assess insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. However, the present invention is not limited to the use of any particular questionnaire.

[0056] Some questionnaires rely on recall over a period of several days or even weeks (recall period). This may be appropriate for diagnosing sleep disorders, but is not always appropriate for assessing the rapid onset of therapeutic effect, especially after treatment. In some questionnaires, the recall period can be modified so that the obtained score reflects the period after treatment. The questionnaires specifically described herein for assessing the therapeutic effect on the sleep of patients with certain conditions rely on a recall period that does not start before the time when the acute psychedelic experience subsides after the last administration. To meet this criterion, the normally applied recall period is modified as necessary.

[0057] Overall sleep quality can be assessed, for example, by the Sleep 50 Questionnaire.

[0058] 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 reflecting some of the most common sleep 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 asked to indicate the extent to which the statement applies to their experience over the past month or another appropriate recall period, using a scale ranging from 1 ("not at all true") to 4 ("extremely true").

[0059] To diagnose a sleep disorder, not only must certain subscales (e.g., insomnia) exceed certain cutoffs, but respondents must also meet cutoffs of at least 3 or 4 ("fairly true" or "very true," respectively) on subscales assessing the impact of sleep dissatisfaction on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0060] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0061] One common questionnaire used to assess sleep disorders is the Pittsburgh Sleep Quality Index (PSQI). Other assessment tools include the Insomnia Severity Questionnaire, the Espie Sleep Disorders Questionnaire, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0062] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another suitable recall period.

[0063] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep onset time, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) time to fall asleep, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0064] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Detailed scoring instructions for the Pittsburgh Sleep Quality Index (PSQI) can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0065] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. The cutoff for the overall score is 5, which distinguishes between individuals with and without sleep problems. A overall score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0066] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a reduction in score, preferably (ii) a reduction to 5 or less.

[0067] The Insomnia Severity Inventory (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective sleep satisfaction, the extent to which insomnia interferes with daily functioning, how significantly the respondent perceives their insomnia compared to others, and the overall level of anxiety caused by sleep problems. Individual responses can be scored from 0 (none) to 4 (very much), with higher total scores corresponding to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 indicates "subthreshold insomnia," 15–21 indicates "clinical insomnia (moderate severity)," and 22–28 indicates "clinical insomnia (severe)" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012, ). The recall period is 2 weeks. Other suitable recall periods can also be used.

[0068] Successful treatment is indicated by (i) a decrease in score (eg, a decrease of more than 7 points), preferably (ii) a decrease below the cutoff for clinically significant insomnia.

[0069] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. By assessing restlessness / arousal, mental overactivity, impact of insomnia, and lack of sleep preparation, the SDQ specifically addresses beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate how often specific statements about insomnia apply to their experience. 1 means "not at all true" and 5 means "very true." Higher scores indicate less accurate beliefs about the causes and associated factors of insomnia (A. Shahid et al., loc. cit.;).

[0070] Successful treatment is indicated by a reduction in score.

[0071] The Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders Assessment Tool is a universal measure for assessing sleep disorders. This assessment tool is available as a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reported sleep quality, sleep depth, and perceived difficulty with falling asleep and staying asleep over a 7-day period.

[0072] Each item in the index is rated on a 5-point scale. A total raw score is calculated by summing the raw scores for each item. The total raw score is then converted to a standardized T-score using a conversion table.

[0073] Successful treatment is indicated by a decrease in the T-score.

[0074] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0075] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. This questionnaire asks respondents to rate how likely they are to fall asleep in eight different relatively inactive situations, such as an afternoon nap or sitting in a car stuck in traffic. Using a scale of 0 to 3 (0 meaning "not likely to doze off at all" and 3 meaning "likely likely to doze off"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating more severe daytime sleepiness. A cutoff score of 10 indicates potentially clinical levels of daytime sleepiness (A. Shahid et al., loc. cit.).

[0076] Successful treatment is indicated by (i) a reduction in score, preferably (ii) a reduction to 10 or less.

[0077] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment in time. The scale consists of only one item, and respondents are asked to select one of seven statements that best describes their current perceived level of sleepiness. Sleepiness is assessed using a scale ranging from 1 (= active, energetic, alert, and wide awake) to 7 (= almost dreamy, prone to falling asleep, unable to stay awake despite efforts) (A. Shahid et al., loc. cit.;).

[0078] Successful treatment is indicated by a reduction in score.

[0079] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0080] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomniac behaviors, assesses their frequency, and also includes an assessment of their consequences (Arnulf et al., A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0081] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0082] One of the common questionnaires for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc. cit.;), which also allows for the selection of an appropriate recall period.

[0083] Successful treatment is indicated by a reduction in score.

[0084] One common questionnaire used to assess sleep-related breathing disorders is the International Restless Legs Syndrome Study Group Scale. This 10-item questionnaire asks respondents to indicate the acute impact of the disorder over the past week using a Likert-type rating. Questions can be categorized into two categories: disease symptoms (nature, intensity, and frequency) and their impact (sleep problems, impairment of daily functioning, and resulting mood changes). Each of the 10 questions asks respondents to rate their RLS experience on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the mildest symptoms. Total scores can range from 0 to 40. As a brief scale with excellent psychometric properties, this assessment tool is considered suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes (A. Shahid et al., loc. cit.).

[0085] Treatment response can be assessed by a reduction in score.

[0086] Scales for assessing psychiatric or neurological disorders A number of scales have been proposed to assess the severity of psychiatric or neurological disorders, and these are based on tests that are either self-administered or administered by a clinician.

[0087] Psychiatric or neurological disorder measures that can be used in accordance with the present invention include measures known in the art for diagnosing and / or monitoring psychiatric or neurological disorders, as described in more detail below.

[0088] Treatment outcome is assessed using one or more indicators or measures at one or more time points after the course of treatment has ended.

[0089] Assessments can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2-3 hours after the last dose. Early assessments can be performed, for example, generally about 2 hours or about 3 hours after the last dose.

[0090] However, assessment of the effect on sleep disorders, or on psychiatric or neurological disorders related to the effect on sleep disorders, can be performed at the earliest on the day after treatment (i.e., Day 1) to ensure that treated patients have had an opportunity to get at least one night's sleep.

[0091] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. Evaluation is performed at least 12 hours after the last dose, and in any case at least one night after the last dose and within 36 hours after the last dose. Evaluation can be performed after about 24 hours.

[0092] Assessment at day 7 or assessment at day 7 refers to assessment on day 7 after dosing (day of dosing is considered day 0). Similar definitions apply to other assessment time points measured in days.

[0093] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response at an early time point (e.g., 2 hours) after drug administration based on an endpoint that is formulated for a longer recall period (e.g., typically 7 days in the MADRS), such endpoint can be reasonably modified (e.g., by changing the recall period of the MADRS to 2 hours and carrying forward the sleep items recorded at baseline before drug administration). The same applies to any other scales used herein to evaluate the therapeutic effect of psychiatric or nervous system disorders, unless a recall period is specifically indicated.

[0094] On the one hand, the influence of the patient's pre-treatment status on any scores recorded after treatment in assessing clinical response must be kept as low as possible, whereas sleep items cannot be assessed 2 hours after drug administration, so the considerations explained above apply at earlier time points.

[0095] 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 the recall period adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0096] Resting-state networks and sleep disorders Brain processes can be investigated 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.

[0097] Functional images of the brain are acquired over several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of this spontaneous signal reveals discrete regions with correlated and anticorrelated fluctuations.

[0098] In this way, resting-state fMRI can be used to characterize large-scale functional networks (so-called resting-state networks (RSNs)), which are spatially distinct groups of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterizing the network of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0099] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0100] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized with respect to aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0101] Resting-state networks (RSNs) have been shown to be involved in various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various disease states, which are associated with altered functional connectivity within a particular resting-state network and / or between one or more regions of one or more additional resting-state networks.

[0102] Altered resting-state networks can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0103] One of the major networks involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during task activity and activated during rest. The DMN is involved in multiple cognitive processes, including higher-order cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN in sleep physiology, changes in DMN activity are particularly important in relation to sleep disorders.

[0104] Dysfunction of the resting-state network can also be observed in psychiatric or neurological disorders, particularly those 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 disorder types I and II; 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; mental and behavioural disorders due to the use of psychoactive substances, 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 neurological disorders associated with HIV, traumatic brain injury or the after-effects of COVID-19.

[0105] Resting-state networks involved in sleep disorders are also influenced by mental or neurological conditions that are the result of certain medical health conditions.

[0106] In patients with insomnia, dysfunctional connectivity has been observed within the default mode network (DMN) and the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain important regions that integrate emotional and physical states, and dysfunctional connectivity within these networks and / or between these networks and other brain regions may underlie patients' arousal, subjective distress, and reduced sleep continuity.

[0107] The default mode network (DMN) is affected in patients with hypersomnia. For example, idiopathic hypersomnia shows significant changes in the precuneus and medial prefrontal cortex, which are key hubs of the default mode network (DMN), and functional connectivity in the DMN correlates with the severity of self-reported sleepiness.

[0108] A study investigating the differences between night-shift and day-shift nurses revealed that circadian rhythm disorders contribute to altered resting-state function in the cerebellum, which is involved in sleep regulation and cognitive functions such as reactivity and vigilance. Furthermore, functional connectivity in the default mode network (DMN) is fundamentally different between morning- and evening-type circadian rhythm phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may cause changes in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various disorders associated with circadian rhythm disorders.

[0109] Although it is technically difficult to perform functional brain imaging during the development of parasomnias, precuneus differences representing NREM parasomnias have been observed in arousal disorders.

[0110] The precuneus is involved in analyzing and integrating visual, auditory, and kinesthetic information, as well as monitoring movement. The precuneus is a subregion of the default mode network (DMN). Therefore, the default mode network is affected in patients with parasomnias.

[0111] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, have shown significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0112] For example, sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in the frontal motor control pathway, a subregion of the default mode network, and also by activity in the cerebellum and thalamus, with further activation in the red nucleus and brainstem.

[0113] In many cases, abnormal functional connectivity of resting-state networks implicated in sleep disorders is also implicated in the conditions described above, and therefore, in accordance with the present invention, affecting these networks via the therapies herein results in improvement of the sleep disorder and, if the patient being treated has a psychiatric or neurological disorder, improvement of the disorder.

[0114] activator The above discussion indicates that such sleep disorders pose a significant disease burden and deserve appropriate treatment.

[0115] The inventors believed that carefully selected hallucinogens may lead to improved treatment of important aspects of sleep disorders, leading to an overall improvement in the condition.

[0116] 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.

[0117] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0118] 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.

[0119] Recently published clinical trials using serotonergic hallucinogens such as LSD, psilocybin, and DMT for the treatment of certain psychiatric disorders (using shamanic ayahuasca tea containing DMT) suggest that these compounds may offer alternatives to currently available medications for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients with depression, which may hinder their use in treating patients with BD.

[0120] 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.

[0121] 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.

[0122] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound to be administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0123] 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.

[0124] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes (e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD) (e.g., bipolar I disorder and bipolar II disorder), psychotic disorders (e.g., schizophrenia), or personality disorders (e.g., schizotypal personality disorder)). Patients suffering from such psychiatric or nervous system disorders, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0129] 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).

[0130] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0131] 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.

[0132] 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 inhalation, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0133] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have investigated the efficacy of 5-MeO-DMT against recombinant human 5-HT7 receptors and their receptors as radioligands.3 Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM. The 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation.

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

[0135] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0136] We investigated the pharmacokinetic properties of 5-MeO-DMT and found rapid absorption and distribution of inhaled 5-MeO-DMT, with peak concentrations and pharmacological effects observed during and immediately after administration.

[0137] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. Titrating doses as disclosed herein does not result in accumulation, and thus does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0138] The properties of 5-MeO-DMT make this compound particularly suitable for treating sleep disorders, especially in patients with psychiatric or neurological disorders.

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

[0140] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

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

[0142] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

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

[0144] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0145] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. 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.

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

[0147] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0148] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0149] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 5-MeO-DMT or a pharmaceutically acceptable salt thereof can be substituted for a prodrug of 5-MeO-DMT or a salt thereof.

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

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

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

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

[0154] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitriloacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitriloacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

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

[0156] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0157] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0158] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration, or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred administration route is inhalation. Preferably, a therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0159] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0160] Buccal or sublingual administration can also be by a pharmaceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in formulations commonly known in the art (e.g., tablets, films, sprays, creams).

[0161] Administration is typically via inhalation of an aerosol. Such an aerosol contains (a) a pharmaceutically acceptable gas and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / L to about 18 mg / L (e.g., about 0.5 mg / L to about 12.5 mg / L, preferably about 1.3 mg / L to about 10 mg / L, particularly about 2 mg / L to about 9 mg / L). The pharmaceutically acceptable gas is preferably air.

[0162] The aerosol particles preferably contain less than 1 wt. % impurities, particularly less than 0.5 wt. % impurities, and more preferably less than 0.5 wt. % 5-MeO-DMT decomposition products, particularly less than 0.2 wt. % 5-MeO-DMT decomposition products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0163] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0164] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0165] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0166] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to generate aerosol particles. The thickness of the thin layer can be less than about 10 μm, particularly less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

[0167] A thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via air passing over the layer, or alternatively, a thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via the solid support.

[0168] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a flow rate of about 12 l / min for about 15 seconds.

[0169] The aerosol particles can be contained in a volume of about 3 liters or less, particularly a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0170] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. Such an aerosol has an aerosol particle mass concentration suitable to allow a therapeutically effective dose of the aerosol to be administered to a patient in a single inhalation.

[0171] The aerosol useful in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is very difficult to predict the conditions suitable for safe, efficient and predictable aerosolization, especially when the aerosol is to be used to systemically deliver the compound to a patient via the lungs. Relevant variables in this context include: a) the dose of the compound; b) the morphological state of the compound that is made aerosolizable (e.g., crystalline form or thin layer form); c) the amount of thermal energy that the compound is exposed to (defined by temperature and exposure duration); and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0172] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products; "efficient" means that the dose is aerosolized to a defined extent, preferably nearly completely or completely, that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., within a single deep breath); and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0173] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) briefly exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature, and c) providing a controlled amount of air so that an aerosol is formed.

[0174] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) can be delivered to a patient by a single inhalation.

[0175] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, which contain less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT degradation product drug by aerosol volume and can be delivered to a patient by a single inhalation, is achieved by specifying a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by the air flow rate and duration of the air flow).

[0176] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, whereby the air is heated. The temperature of the heated air passing over the thin layer can range from about 180°C to about 260°C. The temperature of the air passing over the thin layer can be, in particular, about 210°C.

[0177] Alternatively, the thin layer of 5-MeO-DMT can be exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180°C to about 420°C.

[0178] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is highly pure, being at least 99%, preferably at least 99.5% pure.

[0179] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific effective amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Specific preferred amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0180] The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, a cylinder less than 1.0 mm in diameter, a box less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a high surface area to volume ratio (e.g., greater than 100 per meter) and a high surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0181] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (approximately 400 per meter).

[0182] Several different materials are used to construct solid supports. Such material types include, but are not limited to, metals, inorganic materials, carbon-containing materials, and polymers. Examples of material types are: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene, and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0183] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica-, alumina-, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m), and PEG-1000 (Sigma, St. Louis, Mo.). 2 Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0184] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, particularly less than about 7.5 μm, and the thickness of the thin layer can range from about 0.1 μm to about 10 μm, particularly from 0.3 μm to 7.5 μm.

[0185] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of between about 6 liters per minute and about 40 liters per minute, preferably between about 8 liters per minute and about 16 liters per minute, and the duration of the airflow is selected so that the total aerosol volume does not exceed about 3 liters, which is preferably between about 1 liter and 3 liters (e.g., between 2 liters and 3 liters). For example, at an airflow rate of about 6 liters per minute, the duration of the airflow should be less than about 30 seconds. A specific effective airflow rate and duration is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective airflow rate and duration is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective airflow rate and duration is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0186] The aerosol generation rate is greater than 0.1 mg / sec.

[0187] The aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l).

[0188] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, and most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0189] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT degradation products, preferably less than 0.2% wt of 5-MeO-DMT degradation products.

[0190] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT, organized on a solid support as a thin layer less than 5 microns thick, to a temperature of 210°C for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt of 5-MeO-DMT degradation products; and 3) is capable of being delivered to a patient by a single inhalation.

[0191] Those skilled in the art, knowing the aerosol characteristics and aerosolization conditions defined in the present invention, can identify a suitable vaporization device or system that can achieve the required aerosol characteristics. Examples of such suitable vaporization devices or systems include the Volcano Medic Vaporization System (Storz & Bickel, Germany, for example, as disclosed in EP 0 933 093 B1 and EP 1 884 254 B1 and registered Community design 003387299-0001), which includes a dosage capsule with a related drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA, for example, as disclosed in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The generated aerosol is collected in a balloon, from which it can be inhaled by the patient.

[0192] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (administration schemes).

[0193] The present invention is based in part on the inventors' conclusion that the acute manifestation of a peak psychedelic experience following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, may causally facilitate its therapeutic efficacy in patients with sleep disorders, particularly those with one or more of the aspects defined above, or at least serve as a surrogate behavioral marker of an underlying, unknown therapeutic mechanism.

[0194] Thus, achieving a peak experience more rapidly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0195] 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 could 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 psychedelic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, starting with a low dose generally allows patients to become accustomed to the psychedelic experience and prepare them for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at those higher doses. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the treatment approach and improve overall compliance at the patient population level.

[0196] 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.

[0197] A patient as defined herein having a sleep disorder is treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0198] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for the sleep disorder).

[0199] As defined herein, the dosage of 5-MeO-DMT administered to a patient with a sleep disorder ranges from about 1 mg to 25 mg, or any range therebetween, preferably about 2 mg to 20 mg, and more preferably about 4 mg to 20 mg. Useful specific amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Note that when a range such as "about 1 mg to about 25 mg" is provided herein, the inventors contemplate all discrete values ​​within the range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0200] In a preferred embodiment, the improved method for treating a patient as defined herein having a sleep disorder with a therapeutically effective amount of 5-MeO-DMT comprises a clinical response occurring within about 2 hours after administration of 5-MeO-DMT.

[0201] In a preferred embodiment, the improved method for treating a patient as defined herein having a sleep disorder with a therapeutically effective amount of 5-MeO-DMT comprises a clinical response that occurs within about 2 hours of administration of 5-MeO-DMT and is sustained for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0202] In a preferred embodiment, the improved method for treating a patient as defined herein having a sleep disorder with a therapeutically effective amount of 5-MeO-DMT comprises administering multiple doses of 5-MeO-DMT.

[0203] In a preferred embodiment, the multiple doses of 5-MeO-DMT are administered to the patient in multiple blocks, each block consisting of 2 to 7 doses, with 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.

[0204] 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.

[0205] 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.

[0206] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and treatment block is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific effective amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0207] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or until all administrations within that treatment block have been administered, whichever occurs first.

[0208] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0209] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg, to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increase is 6 mg, the dosage of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage of the third administration will be 18 mg.

[0210] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first treatment, and then increased to a dosage selected from about 8 mg to about 14 mg for the second treatment and to a dosage selected from about 14 mg to about 20 mg for the third treatment, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third treatments are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0211] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration in a first treatment block, and then increased for each subsequent administration in the first treatment block until it reaches 20 mg or all administrations in 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 a dose of 18 mg and therefore the highest dosage in the first treatment block was 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0212] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dosage selected from about 14 mg to about 20 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0213] It will be understood that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0214] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0215] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0216] The occurrence of a "psychedelic peak experience" in a patient can also be identified by achieving at least 60% of the maximum score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0217] In accordance with the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also known as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience?; 2. How out of control was it?; and 3. How profound (i.e., meaningful) was the experience?

[0218] Treatment of sleep disorders and mental and nervous system disorders According to the present invention, it is possible to treat idiopathic sleep disorders, as well as sleep disorders in patients with psychiatric or neurological disorders. In patients with sleep disorders associated with psychiatric or neurological disorders, treatment of sleep disorders according to the present invention results in improvement of the condition associated with the sleep disorder.

[0219] In many cases, the resting state networks involved in sleep disorders are also involved in the conditions described above.

[0220] 5-MeO-DMT can disrupt established functional connectivity patterns in resting-state networks, which resets pathological miswired brain connections as the networks reconnect, establishing new, healthy functional connections with lasting effects.

[0221] The long-lasting effects can be explained by 5-MeO-DMT's neuroplasticity-promoting properties. Specifically, 5-MeO-DMT promotes structural and functional plasticity of synapses, i.e., the sites where neurons connect and communicate with each other. 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, initiating the formation of new synaptic connections. These new connections can be strengthened, weakened, or even lost depending on activity.

[0222] The resulting new synapses then influence the pattern of neuronal activity. We conclude that these reciprocal structural and functional modifications contribute to the proper establishment of networks and the durability of the effects following 5-MeO-DMT administration.

[0223] From a biochemical point of view, 5-MeO-DMT interacts specifically with the 5-HT receptor.

[0224] 5-HT receptors, receptors for the neurotransmitter 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 by these receptors.

[0225] Seven types of 5-HT receptors are expressed in the brain, which can be further divided into several subtypes. Different types and subtypes show different spatial distributions.

[0226] 5-MeO-DMT interacts with several 5-HT receptors, which are involved in mediating the effects of 5-MeO-DMT on resting-state networks and neuronal plasticity.

[0227] In addition to the 5-HT1 and 5-HT2A receptors mentioned above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe this may allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0232] 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 the network and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0233] The inventors further believe that 5-MeO-DMT's binding to 5-HT7 receptors, in addition to 5-HT1A receptors, as two mediators of its effects, including "resetting" functional network connectivity and neuroplasticity, may also have 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.

[0234] Treatment herein results in improvement of the sleep disorder and, if the patient being treated has a psychiatric or neurological disorder, improvement of that disorder.

[0235] Clinical data from studies of patients with treatment-resistant depression (TRD) or postpartum depression (PPD) support that sleep disorders can be effectively treated by administration of 5-MeO-DMT.

[0236] In the TRD study, described in more detail in the Examples section below, the "Decreased Sleep" item on the MADRS, which reflects insomnia, was specifically evaluated.

[0237] The "Decreased Sleep" item on the MADRS refers to the experience of decreased duration or depth of sleep compared to a person's normal pattern when healthy. A score of 0 is assigned if the person sleeps normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, shallow, or disrupted sleep. A score of 4 means at least 2 hours of reduced or disrupted sleep. A score of 6 means less than 2-3 hours of sleep.

[0238] Aggregate scores on the MADRS "Decreased Sleep" item across all eight patients in the study group receiving the individualized dosing plan had a baseline of 25. By day 1 of treatment (the earliest time point to assess the treatment's impact 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.

[0239] The combined MADRS "Decreased Sleep" item scores across all four patients in the 12 mg group had a baseline of 12. On day 1 after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. On day 7 after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0240] Thus, scores for the "decreased sleep" scale, which is particularly relevant to sleep disorders, are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat patients with sleep disorders, particularly psychiatric or neurological disorders.

[0241] Sudden sleep disorder Treating a patient with idiopathic sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the idiopathic sleep disorder.

[0242] Reduction or elimination of the sudden onset sleep disturbance 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.

[0243] The reduction or elimination of the sudden onset sleep disorder 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.

[0244] 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.

[0245] In the case of idiopathic sleep disorder, clinical response can be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least 1 point. Preferably, the CGI-S score decreases by at least 2 points and / or to 0 point. Particularly preferably, the CGI-S score decreases by at least 3 points and / or to 0 point.

[0246] Improvement in episodic sleep disturbance, as reflected by a reduction 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.

[0247] Improvement in episodic sleep disturbance, as reflected by a decrease in CGI-S score, occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0248] The improvement in idiopathic sleep disturbance, 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.

[0249] In one embodiment, improvement in episodic sleep disturbance, 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.

[0250] 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.

[0251] Improvement in idiopathic sleep disturbance, as reflected by a score of at least "much improved" on the CGI-I or PGI-I score, preferably occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0252] 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.

[0253] In one embodiment, improvement in idiopathic sleep disturbance, as reflected by a score of at least "much improved" on the CGI-I 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.

[0254] In the case of idiopathic sleep disorders, improvement may also be assessed by any other measure reflecting changes in quality or quantity of sleep as indicated above, such as, for example, the Pittsburgh Sleep Quality Index (PSQI).

[0255] When assessing treatment outcome using the PSQI, treatment success is indicated by (i) a reduction in the total score, preferably (ii) a reduction to 5 or less. The applicable recall period begins no earlier than the point at which the acute psychedelic experience subsides after the last dose.

[0256] Improvement in idiopathic sleep disturbance, as reflected by a reduction in PSQI total score, particularly a reduction to 5 points or less, preferably occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0257] Such improvement in idiopathic sleep disturbance, as reflected by a reduction in PSQI total score, particularly a reduction to 5 points 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] Improvement in episodic sleep disturbance, as reflected by a reduction in PSQI total score, specifically a reduction to 5 points 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.

[0259] In one embodiment, improvement in episodic sleep disturbance, as reflected by a reduction in PSQI global score, particularly a reduction to 5 points or less, is observed at day 7 and preferably persists through day 14, and more preferably through day 28.

[0260] Sleep disorders associated with psychiatric or neurological disorders Although sleep disorders can be considered a condition requiring treatment regardless of any other conditions, diseases, or symptoms suffered by an individual, some psychiatric or neurological disorders are accompanied by sleep disorders. Notably, the relationship between sleep and psychiatric or neurological disorders is often bidirectional. Not only can psychiatric or neurological disorders adversely affect healthy sleep patterns, but sleep disorders can also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0261] Treatment according to the present invention reduces or eliminates the sleep disorder and preferably also improves the associated psychiatric or neurological disorder.

[0262] A disorder characterized by depressive episodes Several disorders are characterized by depressive episodes.

[0263] A depressive episode is a period of depressed mood and / or lack of pleasure in most activities.

[0264] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present during the same two-week period, represent a change from previous functioning, and at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

[0265] Patients with disorders characterized by depressive episodes may have a treatment-resistant form of the disorder.

[0266] During a depressive episode, patients often have insomnia or hypersomnia.

[0267] Sleep disturbances are included in the diagnostic criteria for disorders characterized by depressive episodes. Sleep disturbances can be assessed as part of the assessment of the MADRS or HAM-D.

[0268] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S.A., & Asberg, M. (1979)). Higher MADRS scores indicate more severe depression.

[0269] The items considered are visible sadness, reported sadness, emotional tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, mood sensitivity, pessimistic thoughts, and suicidal ideation, each of which is given a score of 0 to 6. The total score ranges from 0 to 60.

[0270] The reduced sleep item refers to the experience of sleep disturbance, specifically a decrease in the duration or depth of sleep compared to the individual's normal pattern when healthy. If the patient sleeps normally, a score of 0 is assigned. If the patient has mild difficulty falling asleep or slightly 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.

[0271] 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 items, but the first 17 items (depressed mood, guilt, suicidality, initial insomnia, nighttime insomnia, late-onset insomnia, work and interest, psychomotor retardation, agitation, psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, genital symptoms, hypochondriasis, weight loss, and insight) are used for scoring.

[0272] For most questions, scores range from 0 to 4, with 4 indicating more acute depressive symptoms. For some questions, the range is no higher than 2. Total scores can be tallied and compared to previous scores or to a predefined cutoff score.

[0273] Initial insomnia reflects insomnia early in the night and is scored as 0 if the patient has no trouble falling asleep, 1 if they occasionally have trouble falling asleep (e.g., it takes more than 30 minutes), and 2 if they have trouble falling asleep every night.

[0274] Nocturnal, or nighttime, insomnia is scored as 0 if there is no difficulty falling asleep, 1 if the patient complains of restlessness and disturbed sleep at night, and 2 if the patient wakes up during the night (leaving the bed for purposes other than toileting).

[0275] Late-onset insomnia reflects insomnia in the early morning hours and is scored as 0 if there is no difficulty falling asleep, 1 if the patient wakes up in the early morning hours but is able to fall asleep again, and 2 if they are unable to fall asleep again once they leave bed.

[0276] Patients with disorders characterized by depressive episodes exhibit altered functional connectivity within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, reflection, impaired concentration, and physiological arousal.

[0277] Treating patients with a disease 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, thereby leading to improvement of the disease characterized by depressive episodes.

[0278] The reduction or elimination of sleep disturbances in patients with 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.

[0279] The reduction or elimination of sleep disturbances in patients with a disease characterized by a depressive episode 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.

[0280] In one embodiment, the reduction or elimination of sleep disturbances in a patient having 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.

[0281] Improvement in sleep disturbance in patients with a disorder characterized by a depressive episode, 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.

[0282] The improvement in sleep disturbance in patients with a disease characterized by a depressive episode, as reflected by a reduction in CGI-S score, occurs within 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 a disease characterized by a depressive episode, 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.

[0283] In one embodiment, improvement in sleep disturbance in patients having a disorder characterized by a depressive episode, 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.

[0284] Reduction or elimination of sleep disturbances, particularly sleep depletion, in patients with a disorder characterized by a depressive episode is reflected at least by an improvement in the score on the sleep depletion component of the MADRS 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] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with a disease characterized by a depressive episode, as reflected by an improvement in the score on the MADRS sleep reduction component, 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, particularly sleep reduction, in patients with a disease characterized by a depressive episode, as reflected by an improvement in the score on the MADRS sleep reduction component, preferably persists for at least 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, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients having a disease characterized by a depressive episode, as reflected by an improvement in the score on the MADRS sleep reduction component, 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] Reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with a disorder characterized by a depressive episode is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, particularly a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0288] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with a disease characterized by a depressive episode, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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, particularly sleep reduction, in patients with a disease characterized by a depressive episode, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0289] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with a disorder characterized by a depressive episode, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0290] As shown above, sleep disorder is closely related to the disease characterized by depressive episodes.Therefore, the improvement of sleep disorder will also lead to the improvement of the disease characterized by depressive episodes.Because sleep disorder also affects other aspects of the disease characterized by depressive episodes, the inventors have concluded that the improvement of sleep disorder, particularly the reduction or elimination of sleep loss, will further contribute to the overall improvement of the disease characterized by depressive episodes.

[0291] Improvement in a disorder characterized by depressive episodes in patients who also have sleep disturbances, 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.

[0292] The improvement in the disorder characterized by depressive episodes in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes in patients who also have a 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.

[0293] In one embodiment, improvement in a disorder characterized by depressive episodes in a patient who also has a 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.

[0294] Major depressive disorder (MDD) is a mood disorder that causes persistent low mood and loss of interest. MDD affects a person's feelings, thoughts, and behaviors and can cause a range of emotional and physical problems.

[0295] Patients may have moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. Additionally, patients may be considered to 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.

[0296] Patients with MDD may have a treatment-resistant form of the disorder (TRD).

[0297] 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.

[0298] As indicated above, dysfunctional connectivity in the resting network is also associated with sleep disorders such as insomnia and hypersomnia.

[0299] An estimated three-quarters of all patients with MDD have some form of sleep disorder, such as insomnia or hypersomnia, sometimes both in the same episode. In the DSM-5 criteria, sleep disturbance is one of nine symptoms, at least five of which must be present over time to meet the diagnosis of MDD.

[0300] Sleep disorders in the context of MDD are associated with a risk of suicide and a significant reduction in patients' quality of life.

[0301] Treating patients with MDD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of the MDD.

[0302] Reduction or elimination of sleep disturbances in patients 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.

[0303] 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, 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.

[0304] 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.

[0305] 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.

[0306] The improvement in sleep disturbance in patients with MDD, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0307] 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.

[0308] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with MDD is reflected at least by an improvement in the score on the sleep deprivation component of the MADRS 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.

[0309] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with MDD, as reflected by an improvement in score on at least the MADRS sleep reduction component, occurs within about 24 hours of 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 an improvement in score on at least the MADRS sleep reduction component, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0310] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with MDD, as reflected by an improvement in the score on the MADRS sleep reduction 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.

[0311] Reduction or elimination of sleep disturbances in patients with MDD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0312] The reduction or elimination of sleep disturbances in patients with MDD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 MDD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0313] In one embodiment, the reduction or elimination of sleep disturbances, particularly decreased sleep, in a patient with MDD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0314] As shown above, sleep disorder is closely related to MDD.Therefore, improving sleep disorder will also lead to the improvement of MDD.Because sleep disorder also affects other aspects of MDD, the inventors conclude that improving sleep disorder, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of MDD.

[0315] Improvement in major depressive disorder in patients who also have a 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.

[0316] The improvement in major depressive disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in major depressive disorder in patients who also have a 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.

[0317] In one embodiment, improvement in MDD in patients who also have a 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.

[0318] Sleep disorders are also associated with postpartum depression (PPD).

[0319] More than 50% of women may experience short-term depression or tearfulness after giving birth. However, some women may develop PPD, a debilitating mood disorder that occurs during pregnancy or within four weeks after giving birth. Epidemiological studies estimate the prevalence of PPD to be around 15%.

[0320] Patients may have moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. Additionally, patients may have severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0321] Patients treated according to the present invention may have a score of 20 or greater on the Montgomery-Asberg Depression Rating Scale (MADRS) or a score of 16 or greater on the 17-item Hamilton Depression Rating Scale (HAM-D).

[0322] 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.

[0323] 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.

[0324] Patients with PPD may have a treatment-resistant form of the disorder.

[0325] Postpartum depression not only affects the mother's overall health, but also the way she interacts with her child and ultimately their development.

[0326] Sleep disturbances are a commonly reported symptom during pregnancy and are significantly associated with the presence of depressive symptoms: women with poor sleep quality are 3.34 times more likely to suffer from depression compared with women with good sleep quality.

[0327] The presence of sleep disturbances during pregnancy is itself a precursor to PPD.

[0328] Studies have shown that changes in sleep quality, rather than the hormonal milieu, are associated with the recurrence and severity of PPD.

[0329] PPD can be assessed by the Edinburgh Postnatal Depression Scale (EPDS), which assesses the mother's feelings over the past seven days. Insomnia as a result of feelings of unhappiness is one of the 10 questions assessed by this questionnaire. The scale ranges from "0" (no, not at all) to "3" (yes, most of the time). At a threshold level of 13 points, sleep disturbances can be considered a fundamental part of the PPD diagnosis.

[0330] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition. PPD has been associated with dysfunctional resting-state network connectivity within and / or between, for example, the default mode network and the frontoparietal network.

[0331] Treating patients with PPD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of the PPD.

[0332] Reduction or elimination of sleep disturbances in patients 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.

[0333] 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, 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.

[0334] 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.

[0335] 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.

[0336] The improvement in sleep disturbance in patients with PPD, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0337] 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.

[0338] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with PPD is reflected at least by an improvement in the score on the sleep deprivation component of the MADRS 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.

[0339] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with PPD, as reflected by an improvement in the score on the MADRS sleep reduction component, 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, particularly sleep reduction, in patients with PPD, as reflected by an improvement in the score on the MADRS sleep reduction component, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0340] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with PPD, as reflected by an improvement in the score on the MADRS sleep reduction 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.

[0341] Reduction or elimination of sleep disturbances in patients with PPD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] The reduction or elimination of sleep disturbances in patients with PPD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 PPD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0343] In one embodiment, the reduction or elimination of sleep disturbances, particularly decreased sleep, in a patient with PPD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0344] As shown above, sleep disorder is closely related to PPD.Therefore, the improvement of sleep disorder will also lead to the improvement of PPD.Sleep disorder also affects other aspects of PPD, so the inventors conclude that the improvement of sleep disorder, particularly the reduction or elimination of sleep loss, will further contribute to the overall improvement of PPD.

[0345] Improvement in postpartum depression in patients who also have sleep disturbances, 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.

[0346] The improvement in postpartum depression in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, 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.

[0347] In one embodiment, improvement in PPD in patients who also have a 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.

[0348] In one embodiment, improvement in PPD in patients who also have sleep disturbances, 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.

[0349] Furthermore, sleep disturbances impair maternal functional status.

[0350] Maternal functioning status can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index is designed to measure functional status one year after delivery. The BIMF is a self-reported measure of functional status consisting of 20 items. Each item is assigned a score from 0 to 6, with a maximum total score of 120. The higher the score, the better the assessment of maternal functioning status.

[0351] The BIMF identifies the following key areas of maternal functioning in the postpartum period: self-care, infant care, maternal-infant interaction, maternal mental health, social support, management skills, and adaptation skills.

[0352] A BIMF score of 95 or less is considered herein to indicate slightly impaired maternal functional status, a score of 80 or less is considered herein to indicate impaired maternal functional status, and a score of 65 or less is considered herein to indicate severely impaired maternal functional status.

[0353] The inventors have determined that an increased score on the "reduced sleep" item of the MADRS negatively impacts both aspects of maternal functional status (the mother's ability to interact with her infant and to care for herself). An increased score on the "reduced sleep" item of the MADRS impairs self-care, mental well-being, and ability to manage.

[0354] Increased scores on the MADRS sleep loss item impair mental health, social support, and co-ordination, whereas improvements on this MADRS item lead to improvements in maternal functioning, specifically in the BIMF domains of self-care, mental health, and / or co-ordination.

[0355] The inventors concluded that treating patients with PPD with 5-MeO-DMT can result in improvement of sleep disturbances, specifically reduction or elimination of sleep reduction.

[0356] The inventors further concluded that reducing or eliminating sleep reduction through treatment of PPD patients not only leads to a decrease in the total MADRS score, but also to an improvement in maternal functioning status as reflected by an increase in the BIMF score.

[0357] The total score of BIMF should improve by 10% or more, preferably 20% or more.

[0358] Improvement in maternal functioning status in patients with PPD is reflected at least by 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.

[0359] The improvement in maternal functional status in patients with PPD, as reflected by at least an improvement in BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functional status in patients with PPD, as reflected by at least an improvement in BIMF total score, persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0360] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic depressive state. It is diagnosed when a person experiences depressed mood for most of the day for at least two years, with symptom-free periods of less than two months.

[0361] While depressed, two or more of the following must be present: 1. Feeling hopeless, 2. Low energy or fatigue, 3. Low self-esteem, 4. Decreased sleep (insomnia) or increased sleep (hypersomnia), 5. Loss of appetite or overeating, 6. Difficulty making decisions or concentrating.

[0362] Patients with persistent depressive disorder may have a treatment-resistant form of the disorder.

[0363] Patients with persistent depressive disorder exhibit altered functional connectivity within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal. Dysfunctional 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.

[0364] Treating patients with persistent depressive disorder and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of MDD.

[0365] 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.

[0366] The reduction or elimination of sleep disturbances in patients with persistent depressive disorder 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.

[0367] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0368] 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.

[0369] The improvement in sleep disturbance in patients with persistent depressive disorder, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0370] 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.

[0371] Reduction or elimination of sleep disturbances, particularly sleep depletion, in patients with persistent depressive disorder is reflected at least by an improvement in the score on the sleep depletion component of the MADRS 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] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with persistent depressive disorder, as reflected by an improvement in at least the score on the MADRS sleep reduction component, 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, particularly sleep reduction, in patients with persistent depressive disorder, as reflected by an improvement in at least the score on the MADRS sleep reduction component, preferably persists for at least 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, the reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with persistent depressive disorder, as reflected by an improvement in the score on the MADRS sleep reduction 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.

[0374] Reduction or elimination of sleep disturbances in patients with persistent depressive disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0375] The reduction or elimination of sleep disturbances in patients with persistent depressive disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 persistent depressive disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0376] 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 reduction to 5 points 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.

[0377] As shown above, sleep disorder is closely related to persistent depressive disorder.Therefore, the improvement of sleep disorder will also lead to the improvement of persistent depressive disorder.Because sleep disorder also affects other aspects of persistent depressive disorder, the inventors have concluded that the improvement of sleep disorder, in particular the reduction or elimination of sleep loss, will further contribute to the overall improvement of persistent depressive disorder.

[0378] Improvement in persistent depressive disorder in patients who also have sleep disturbances, 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.

[0379] The improvement in persistent depressive disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in persistent depressive disorder in patients who also have a 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.

[0380] In one embodiment, improvement in persistent depressive disorder in patients who also have a 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.

[0381] Sleep disturbances are also a common symptom of seasonal affective disorder.

[0382] Seasonal affective disorder is a mood disorder with a seasonal pattern; symptoms often begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0383] Patients with seasonal affective disorder may have a treatment-resistant form of the disorder.

[0384] People with seasonal affective disorder may feel excessive daytime sleepiness, sleep longer than usual at night, have difficulty waking from long sleep periods, or need multiple naps throughout the day, which may not relieve the sleepiness. Nightmares are also common in people with seasonal affective disorder.

[0385] Monthly and seasonal sleep duration is a core endpoint in the assessment of seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire (SPAQ), which asks participants to rate seasonal changes in sleep, social interactions, mood, weight, appetite, and energy, with sleep being asked in three of six questions.

[0386] Patients with seasonal affective disorder have altered resting-state activity involving sensorimotor, attention, and visual processing compared to healthy individuals.

[0387] Patients with seasonal affective disorder exhibit altered functional connectivity within and / or among several brain regions involved in cognitive processes related to processing, regulation, emotional memory, reflection, impaired concentration, and physiological arousal. Dysfunctional connectivity is observed within and / or among the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0388] Treating patients with seasonal affective disorder and associated sleep disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates seasonal affective disorder, leading to improvement of the seasonal affective disorder.

[0389] The reduction or elimination of sleep disturbances in patients with 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.

[0390] The reduction or elimination of sleep disturbances in a patient with 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 with seasonal affective disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0391] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0392] Improvement in sleep disturbance 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.

[0393] The improvement in sleep disturbance in patients with seasonal affective disorder, as reflected by a reduction in CGI-S score, occurs within 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.

[0394] 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.

[0395] Reduction or elimination of sleep disturbances, particularly sleep depletion, in a patient with seasonal affective disorder is reflected at least by an improvement in the score on the sleep depletion component of the MADRS 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.

[0396] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with seasonal affective disorder, as reflected by an improvement in the score on the MADRS sleep reduction component, 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, particularly sleep reduction, in patients with seasonal affective disorder, as reflected by an improvement in the score on at least the MADRS sleep reduction component, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0397] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in a patient with seasonal affective disorder, as reflected by an improvement in the score on the MADRS sleep reduction 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.

[0398] Reduction or elimination of sleep disturbances in patients with seasonal affective disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0399] The reduction or resolution of sleep disturbances in patients with seasonal affective disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of sleep disturbances in patients with seasonal affective disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0400] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep reduction, in a patient with seasonal affective disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0401] As shown above, sleep disorder is closely related to seasonal affective disorder.Therefore, the improvement of sleep disorder will also lead to the improvement of seasonal affective disorder.Because sleep disorder also affects other aspects of seasonal affective disorder, the inventors have concluded that the improvement of sleep disorder, particularly the reduction or elimination of sleep loss, will further contribute to the overall improvement of seasonal affective disorder.

[0402] Improvement in seasonal affective disorder in patients who also have sleep disturbances, 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.

[0403] The improvement in seasonal affective disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder in patients who also have a 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.

[0404] In one embodiment, improvement in seasonal affective disorder in patients who also have a 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.

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

[0406] Patients with BD may have a treatment-resistant form of the disorder.

[0407] BD is classified as bipolar I disorder if there has been at least one manic episode, with or without a depressive episode. BD is classified as bipolar II disorder if there has been at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode. If these symptoms are due to drugs or medical problems, it is not diagnosed as bipolar disorder.

[0408] Patients with BD, whether specifically diagnosed with bipolar II disorder or bipolar I disorder, are currently experiencing a major depressive episode.

[0409] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). Patients may have a total score of 19 or greater, such as 24 or greater, particularly 37 or greater.

[0410] Additionally or alternatively, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19 or more, such as 24 or more, particularly 37 or more.

[0411] Sleep disturbances, including variations in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities, are particularly noted in patients with BD, including bipolar I disorder and bipolar II disorder.

[0412] Loss of sleep cravings is often an indicator of the onset of a manic episode.

[0413] Disruption of the normal sleep / wake cycle has been implicated in the psychopathology of bipolar disorder, and dysregulated circadian rhythms are considered biomarkers of bipolar disorder.

[0414] During manic episodes, sleep disturbances are present in 69–99% of patients.

[0415] Sleep disturbances contribute to early recurrence of episodes and reduced quality of life (visible reduction in healthy behavior and increased risk of suicide).

[0416] 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 assess the severity of depressive and / or mixed symptoms exhibited by patients during the current and past few days based on a clinical interview. If there is a discrepancy between current and past few days' symptoms, the current symptoms must be reflected in the rating. The scale contains 20 questions, with a maximum score of 60. Higher scores indicate greater severity.

[0417] 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 thoughts, feelings of guilt, psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation.

[0418] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3 points.

[0419] 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).

[0420] Insomnia (reduction in total sleep time) is scored as 0 (no reduction in total sleep time), 1 (mild, reduction of up to 2 hours), 2 (moderate, 2-4 hours), or 3 (severe, more than 4 hours).

[0421] Separately, hypersomnia is rated on a scale of 0 (no increase in total sleep time, including daytime sleep), 1 (mild, less than 2 hours or normal amount but no restorative effect), 2 (moderate, 2-4 hours), and 3 (severe, more than 4 hours).

[0422] Patients with bipolar disorder exhibit characteristic abnormal intrinsic organization and interconnections of resting-state networks. Compared with healthy controls, resting-state functional magnetic resonance imaging studies have shown 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.

[0423] Treating patients with BD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of BD.

[0424] 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.

[0425] 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, 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.

[0426] In one embodiment, 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.

[0427] 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.

[0428] The improvement in sleep disturbance in patients with BD, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0429] 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.

[0430] Reduction or elimination of sleep disturbances in patients with BD may be reflected by at least an improvement in the BDRS sleep disturbance item 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.

[0431] The reduction or resolution of sleep disturbances in patients with BD, as reflected by an improvement in the score on the sleep disturbances component of the BDRS, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of sleep disturbances in patients with BD, as reflected by an improvement in the score on the sleep disturbances component of the BDRS, preferably persists for at least 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, reduction or resolution of sleep disturbances in patients with BD, as reflected by an improvement in the score on the sleep disturbances component of the BDRS, 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] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with BD is reflected at least by an improvement in the score on the sleep deprivation component of the MADRS on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0434] The reduction or elimination of sleep disturbances, particularly sleep reduction, in patients with BD, as reflected by an improvement in the score on the MADRS sleep reduction component, 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, particularly sleep reduction, in patients with BD, as reflected by an improvement in the score on the MADRS sleep reduction component, preferably persists for at least 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.

[0435] In one embodiment, the reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients with BD, as reflected by an improvement in the score on the MADRS sleep deprivation 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.

[0436] Reduction or elimination of sleep disturbances in patients with BD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0437] The reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0438] In one embodiment, reduction or elimination of sleep disturbances in patients with BD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0439] Reduction or elimination of sleep disturbances, particularly increased total sleep time, in patients with BD is reflected at least by an improvement in the score on the hypersomnia component of the BDRS on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0440] The reduction or elimination of sleep disturbances, particularly increased total sleep time, in patients with BD, as reflected by an improvement in the score on the hypersomnia component of the BDRS, 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, particularly increased total sleep time, in patients with BD, as reflected by an improvement in the score on the hypersomnia component of the BDRS, preferably persists for at least 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.

[0441] In one embodiment, reduction or elimination of sleep disturbances, particularly increased total sleep time, in patients with BD, as reflected by an improvement in the score on the hypersomnia component of the BDRS, 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.

[0442] As shown above, sleep disorders are closely related to BD. Therefore, improving sleep disorders will also lead to improvement of BD. Because sleep disorders also affect other aspects of BD, the inventors concluded that improving sleep disorders will further contribute to the overall improvement of BD.

[0443] Improvement in BD in patients who also have sleep disturbances, 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.

[0444] The improvement in BD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BD in patients who also have a 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.

[0445] In one embodiment, improvement in BD in patients who also have a 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.

[0446] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include feelings of apprehension, panic, and fear, as well as sweating and increased heart rate. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system that involves preparation for an anticipated event or situation that is perceived as threatening.

[0447] Patients with anxiety disorders may have treatment-resistant forms of the disorder.

[0448] Patients with anxiety disorders often experience sleep disturbances, particularly insomnia. Excessive worry and fear make it difficult to fall asleep and stay asleep throughout the night.

[0449] Insomnia can exacerbate anxiety, creating a vicious cycle of insomnia and anxiety.

[0450] The severity of anxiety disorders can be assessed using the 14-item Hamilton Anxiety Scale (HAM-A). Each item is defined by a set of symptoms and measures mental anxiety (mental arousal and psychological distress) and somatic anxiety (physical complaints related to anxiety). Item 4 is "Insomnia," defined as "difficulty falling asleep, intermittent sleep, insufficient sleep, and fatigue upon awakening, dreams, nightmares, and night terrors." Each item is rated from 0 (no symptoms) to 4 (severe), with a total score ranging from 0 to 56.

[0451] Sleep disturbances can also be assessed using, for example, the Pittsburgh Sleep Quality Index (PSQI) global score.

[0452] Anxiety disorders are associated with altered functional connectivity of resting-state networks. In anxiety disorders, abnormalities are observed in the default mode network (DMN), which influences self-awareness; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. The balance of resting states within and / or between these networks, e.g., the SMN and SN relative to the DMN, may be abnormal in various anxiety disorders.

[0453] Altered functional connectivity of affected networks is also associated with sleep disturbances, and anxiety disorders are associated with sleep disturbances.

[0454] Treating patients with anxiety disorders and associated sleep disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which in turn leads to improvement of the anxiety disorder.

[0455] The reduction or elimination of sleep disturbances in patients with anxiety disorders 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.

[0456] The reduction or elimination of sleep disturbances in a patient with 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 with an anxiety disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0458] Improvement in sleep disturbance in patients with anxiety 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.

[0459] The improvement in sleep disturbance in patients with anxiety disorders, as reflected by a reduction in CGI-S score, occurs within 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 anxiety 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.

[0460] In one embodiment, improvement in sleep disturbance in patients with anxiety disorders, 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.

[0461] Reduction or elimination of sleep disturbances in patients with anxiety disorders is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0462] The reduction or elimination of sleep disturbances in a patient with an anxiety disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 an anxiety disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0463] In one embodiment, the reduction or elimination of sleep disturbances in a patient with an anxiety disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0464] As shown above, sleep disorder occurs in patients with anxiety disorder.Therefore, improving sleep disorder will also lead to the improvement of anxiety disorder.Because sleep disorder also affects other aspects of anxiety disorder, the inventors conclude that improving sleep disorder will further contribute to the overall improvement of anxiety disorder.

[0465] Improvement in anxiety disorders in patients who also have sleep 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.

[0466] The improvement in the anxiety disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the anxiety disorder in patients who also have a 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.

[0467] In one embodiment, improvement in anxiety disorder in patients who also have a 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.

[0468] Separation anxiety disorder is characterized by excessive anxiety about being separated from home and / or from people with whom the sufferer has strong emotional ties.

[0469] Separation situations can cause great distress to patients, and they may be unable to attend school or work because of the separation. Patients with separation anxiety disorder may also have excessive anxiety about unfortunate events happening to important people in their lives, such as family members.

[0470] Patients with separation anxiety disorder may have a treatment-resistant form of the disorder.

[0471] Separation anxiety disorder is associated with sleep disturbances. In fact, sleep disturbances are part of the diagnostic criteria for separation anxiety disorder. Sleep disturbances in patients with separation anxiety disorder include nightmares, difficulty falling asleep and staying asleep, early morning awakenings, and parasomnias.

[0472] The severity of separation anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, which can further be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0473] Sleep disturbances in separation anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0474] Anxiety disorders are associated with altered functional connectivity of resting-state networks. In anxiety disorders, abnormalities are observed in the default mode network (DMN), which influences self-awareness; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. The balance of resting states within and / or between these networks, e.g., the SMN and SN relative to the DMN, may be abnormal in various anxiety disorders.

[0475] Altered functional connectivity of the affected networks is also associated with sleep disturbances, and separation anxiety disorder is associated with sleep disturbances.

[0476] Treating patients with separation anxiety disorder and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of the separation anxiety disorder.

[0477] Reduction or elimination of sleep disturbances in patients with 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.

[0478] The reduction or elimination of sleep disturbances in a patient with 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 with separation 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.

[0479] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0480] 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.

[0481] The improvement in sleep disturbance in patients with separation anxiety disorder, as reflected by a decrease in CGI-S score, occurs within 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.

[0482] 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.

[0483] Reduction or elimination of sleep disturbances in patients with separation anxiety disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] The reduction or elimination of sleep disturbances in patients with separation anxiety disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 or less, 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 separation anxiety disorder, as reflected by an improvement in the PSQI global 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.

[0485] In one embodiment, the reduction or elimination of sleep disturbances in patients with separation anxiety disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0486] As shown above, sleep disturbance is an important symptom of patients with separation anxiety disorder.Therefore, improving sleep disturbance will also lead to the improvement of separation anxiety disorder.Because sleep disturbance also affects other aspects of separation anxiety disorder, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of separation anxiety disorder.

[0487] Improvement in separation anxiety disorder in patients who also have a 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.

[0488] The improvement in separation anxiety disorder in patients who also have a sleep disorder, as reflected by a decrease in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in separation anxiety disorder in patients who also have a 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.

[0489] In one embodiment, improvement in separation anxiety disorder in patients who also have a 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.

[0490] Agoraphobia is the fear of situations or places that cause feelings of panic, entrapment, helplessness, or embarrassment.

[0491] Patients with agoraphobia may be unable to leave the house. For some, even the thought of leaving the house can cause so much anxiety that it triggers avoidance behavior. Fears of crowds, travel, elevators, cinemas, shopping malls, etc. can cause significant problems.

[0492] Agoraphobic patients may also experience recurrent panic attacks.

[0493] Patients with agoraphobia may have a treatment-resistant form of the disorder.

[0494] Agoraphobia is associated with sleep disorders such as insomnia.

[0495] The severity of agoraphobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, which can further be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0496] Sleep disturbance in agoraphobia can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0497] Functional magnetic resonance imaging of individuals with agoraphobia has revealed altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0498] Treating patients with agoraphobia and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of agoraphobia.

[0499] The reduction or elimination of sleep disturbances in patients with 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.

[0500] The reduction or elimination of sleep disturbances in a patient with 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 with agoraphobia preferably persists for at least 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.

[0501] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0502] 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.

[0503] The improvement in sleep disturbance in patients with agoraphobia, as reflected by a reduction in CGI-S score, occurs within 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.

[0504] In one embodiment, improvement in sleep disturbance in patients with 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.

[0505] Reduction or elimination of sleep disturbance in patients with agoraphobia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0506] The reduction or elimination of sleep disturbances in patients with agoraphobia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 agoraphobia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0507] In one embodiment, the reduction or elimination of sleep disturbances in a patient with agoraphobia, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0508] As mentioned above, sleep disturbance is an important symptom of patients with agoraphobia. Therefore, improving sleep disturbance will also lead to improvement of agoraphobia. Because sleep disturbance also affects other aspects of agoraphobia, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of agoraphobia.

[0509] Improvement in agoraphobia in patients who also have a 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.

[0510] The improvement in agoraphobia in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in agoraphobia in patients who also have a 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.

[0511] In one embodiment, improvement in agoraphobia in patients who also have a 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.

[0512] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control anxiety about a wide range of situations and problems. People with GAD may anticipate disasters and experience excessive anxiety about money, health, family, work, or other problems.

[0513] Generalized anxiety disorder is diagnosed when persistent anxiety about everyday challenges is excessive and out of proportion to the perceived threat. Patients with GAD typically experience excessive fear that can persist for months to years.

[0514] GAD interferes with social, occupational, or other important areas of functioning.

[0515] Patients with GAD may have a treatment-resistant form of the disorder.

[0516] A key feature of GAD is sleep disturbance, specifically difficulty falling asleep or staying asleep, or restless, inadequate sleep. Sleep disturbance is associated with significant dysfunction in GAD. In the DSM-5 criteria, sleep disturbance is one of six symptoms, at least three of which must be present over time to meet the diagnosis of GAD.

[0517] The severity of generalized anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, which can further be used as a measure of outcome of treatment according to the present invention by administering the scale before and after treatment.

[0518] Sleep disturbances in generalized anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0519] GAD patients also exhibit alterations in functional connectivity, particularly within the default mode network, and alterations in functional connectivity within affected networks are also associated with sleep disturbances.

[0520] Treating patients with GAD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement in GAD.

[0521] Reduction or elimination of sleep disturbances in patients 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.

[0522] 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, 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.

[0523] 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.

[0524] 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.

[0525] The improvement in sleep disturbance in patients with GAD, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0526] 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.

[0527] Reduction or elimination of sleep disturbances in patients with GAD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0528] The reduction or elimination of sleep disturbances in patients with GAD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0529] In one embodiment, reduction or elimination of sleep disturbances in patients with GAD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0530] As mentioned above, sleep disturbance is one of the most common complaints of GAD patients. Therefore, improving sleep disturbance will also lead to improvement of GAD. Because sleep disturbance also affects other aspects of GAD, the inventors concluded that improving sleep disturbance, specifically reducing or eliminating sleep loss, will further contribute to the overall improvement of GAD.

[0531] Improvement in GAD in patients who also have sleep disturbances, as reflected by a reduction 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.

[0532] The improvement in GAD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in GAD in patients who also have a 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.

[0533] In one embodiment, improvement in GAD in patients who also have a 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.

[0534] Social anxiety disorder (SAD), also known as social phobia, is one of the most common anxiety disorders. SAD is characterized by intense anxiety or fear of being evaluated, negatively judged, or rejected by others in social or performance situations. This can lead to avoidance of social situations and interfere with school, work, or relationships.

[0535] Patients with SAD may have a treatment-resistant form of the disorder.

[0536] Sleep disturbances (primarily insomnia) are extremely common in patients with social anxiety disorder, as there is a bidirectional relationship between sleep disturbances (primarily insomnia) and anxiety.

[0537] The severity of social anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, which can further be used as a measure of outcome of treatment according to the present invention by administering the scale before and after treatment.

[0538] Sleep disturbances in social anxiety disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0539] Insomnia is reflected by altered functional connectivity within and / or between resting-state networks such as the default mode network and the salience network, networks in which altered functional connectivity is observed in patients with SAD.

[0540] Treating patients with SAD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of SAD.

[0541] Reduction or elimination of sleep disturbances in patients 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.

[0542] The reduction or elimination of sleep disturbances in patients with SAD 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.

[0543] 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.

[0544] 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.

[0545] The improvement in sleep disturbance in patients with SAD, as reflected by a reduction in CGI-S score, occurs within 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.

[0546] 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.

[0547] Reduction or elimination of sleep disturbances in patients with SAD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0548] The reduction or elimination of sleep disturbances in patients with SAD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 SAD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0549] 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 points 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.

[0550] As shown above, sleep disturbance is a particularly important symptom in SAD patients.Therefore, improving sleep disturbance will also lead to the improvement of SAD.Because sleep disturbance also affects other aspects of SAD, the inventors conclude that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of SAD.

[0551] Improvement in SAD in patients who also have sleep disturbances, 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.

[0552] The improvement in SAD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in SAD in patients who also have a 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.

[0553] In one embodiment, improvement in SAD in patients who also have a 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.

[0554] Patients with panic disorder experience spontaneous panic attacks with sudden onset of intense fear or discomfort that peaks within minutes.

[0555] Panic attacks are characterized by many physical symptoms of anxiety, such as sweating, shaking, trembling, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0556] Additionally, the disorder is often accompanied by anxiety about future panic attacks, and sufferers may become intensely preoccupied with the fear of recurring attacks.

[0557] Patients with panic disorder may have a treatment-resistant form of the disorder.

[0558] Sleep disorders (especially insomnia and hypersomnia) are extremely common in patients with panic disorder.

[0559] People with panic disorder may also experience nocturnal panic attacks, which are distinct from night terrors. Nocturnal panic attacks may occur without any trigger and often make it difficult to fall back asleep.

[0560] The severity of panic disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, and which can further be used as a measure of the outcome of treatment according to the present invention by administering the scale before and after treatment.

[0561] Sleep disturbances in panic disorder can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0562] Patients with panic disorder exhibit altered functional connectivity within and / or between the default mode network and the somatomotor network. Altered functional connectivity within and / or between resting-state networks, specifically the default mode network, also characterize insomnia and hypersomnia.

[0563] Treating patients with panic disorder, 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 panic disorder and leads to improvement in seasonal affective disorder.

[0564] Reduction or elimination of sleep disturbances in patients with 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.

[0565] The reduction or elimination of sleep disturbances in patients with 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 with panic disorder persists preferably for at least 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, the reduction or elimination of sleep disturbances in a patient with 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.

[0567] Improvement in sleep disturbance in patients with 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.

[0568] The improvement in sleep disturbance in patients with panic disorder, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0569] In one embodiment, improvement in sleep disturbance in patients with 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.

[0570] Reduction or elimination of sleep disturbances in patients with panic disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0571] The reduction or elimination of sleep disturbances in patients with panic disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 panic disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0572] In one embodiment, the reduction or elimination of sleep disturbances in patients with panic disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0573] As mentioned above, sleep disorders are very common in patients with panic disorder. Therefore, improving sleep disorders will also lead to improvement of panic disorder. Because sleep disorders also affect other aspects of panic disorder, the inventors have concluded that improving sleep disorders, particularly reducing or eliminating insomnia and / or hypersomnia, will further contribute to the overall improvement of panic disorder.

[0574] Improvement in panic disorder in patients who also have a 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.

[0575] The improvement in panic disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in panic disorder in patients who also have a 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.

[0576] In one embodiment, improvement in panic disorder in patients who also have a 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.

[0577] A phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation. Patients with a phobia experience extreme anxiety when anticipating or being exposed to the feared stimulus. Phobias include animal-type phobias (spiders, snakes, dogs), environmental phobias (tornadoes, heights, water, fire), blood and syringe-type phobias (needles, medical procedures), situational phobias (flying, closed spaces), and other types of phobias (phobias that do not fit into any of the above categories).

[0578] Phobias generally result in an acute onset of fear, usually present for six months or more. Patients go to great lengths to avoid the feared stimulus. The fear and avoidance behaviors are associated with significant distress and / or impair occupational, academic, or social functioning.

[0579] Patients with phobias may have a treatment-resistant form of the disorder.

[0580] Evidence suggests that patients with phobias are more likely to have sleep disorders.

[0581] The severity of the phobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbance is part, which can further be used as a measure of the outcome of treatment according to the invention by administering the scale before and after treatment.

[0582] Sleep disturbance in phobias can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0583] Phobias are also reflected in altered functional connectivity of resting-state networks, such as networks involving the amygdala and insular cortex, such as the salience network, which also plays a role in insomnia.

[0584] Treating patients with phobias and associated sleep disturbances, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of the phobia.

[0585] The reduction or elimination of sleep disturbances in patients with phobias 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.

[0586] The reduction or elimination of sleep disturbances in a patient with a phobia 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.

[0587] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0588] Improvement in sleep disturbance in patients with 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.

[0589] The improvement in sleep disturbance in patients with phobia, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0590] In one embodiment, improvement in sleep disturbance in patients with 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.

[0591] Reduction or elimination of sleep disturbances in patients with phobias is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0592] The reduction or elimination of sleep disturbances in a patient with a phobia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 a phobia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0593] In one embodiment, a reduction or elimination of sleep disturbances in a patient with a phobia, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0594] As mentioned above, patients with phobias are more likely to have sleep disorders. Therefore, improving sleep disorders will also lead to improvement of phobias. Because sleep disorders also affect other aspects of phobias, the inventors concluded that improving sleep disorders, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of phobias.

[0595] Improvement in phobia in patients who also have sleep disturbances, 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.

[0596] The improvement in phobia in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in phobia in patients who also have a 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.

[0597] In one embodiment, improvement in phobia in patients who also have a 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.

[0598] Substance / medication-induced anxiety disorder is an anxiety disorder in which anxiety or panic occurs after use of alcohol, drugs of abuse, or medications, or after exposure to toxins. Substance / medication-induced anxiety disorder causes prominent symptoms of panic or anxiety and can occur during intoxication or withdrawal from a substance or medication.

[0599] The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0600] Individuals with substance / medication-induced anxiety disorder may feel anxious and worried while using the substance or medication or immediately after, experience symptoms of negative thinking, have problems with concentration or memory, fear of losing their mind or going insane or dying, lose weight due to gastrointestinal problems, have chills, hot flashes, sweating, trembling, numbness, a racing heartbeat, difficulty breathing, difficulty swallowing, or chest pain.

[0601] Patients with substance / medication-induced anxiety disorders may have a treatment-resistant form of the disorder.

[0602] Substance / medication-induced anxiety disorders are also associated with sleep disturbances: patients may have difficulty falling asleep or wake up frequently during the night.

[0603] The severity of substance / medication-induced anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which assessment of sleep disturbance is part, and which can further be used as a measure of outcome of treatment according to the present invention by administering the scale before and after treatment.

[0604] Sleep disturbances in substance / medication-induced anxiety disorders can also be assessed by the Pittsburgh Sleep Quality Index (PSQI).

[0605] Functional magnetic resonance imaging of individuals with substance / medication-induced anxiety disorders has revealed altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0606] Treating patients with substance / medication-induced anxiety disorder, 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 substance / medication-induced anxiety disorder and leads to improvement in separation anxiety disorder.

[0607] Reduction or elimination of sleep disturbances in patients with substance / medication-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.

[0608] The reduction or elimination of sleep disturbances in patients with substance / medication-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 with substance / medication-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.

[0609] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0610] 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.

[0611] The improvement in sleep disturbance in patients with substance / medication-induced anxiety disorder, as reflected by a reduction in CGI-S score, occurs within 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 / medication-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.

[0612] 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.

[0613] Reduction or elimination of sleep disturbances in patients with substance / medication-induced anxiety disorders is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0614] The reduction or elimination of sleep disturbances in patients with substance / medication-induced anxiety disorder, as reflected by an improvement in PSQI global score, particularly a reduction to 5 points or less, 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 / medication-induced anxiety disorder, as reflected by an improvement in PSQI global score, particularly a reduction to 5 points 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.

[0615] In one embodiment, 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 points 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.

[0616] As shown above, sleep disturbance is an important symptom of patients with substance / medication-induced anxiety disorder.Therefore, improving sleep disturbance will also lead to the improvement of substance / medication-induced anxiety disorder.Because sleep disturbance also affects other aspects of substance / medication-induced anxiety disorder, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of substance / medication-induced anxiety disorder.

[0617] Improvement in substance / medication-induced anxiety disorders in patients who also have sleep disturbances, 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.

[0618] The improvement in substance / medication-induced anxiety disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in substance / medication-induced anxiety disorder in patients who also have a 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.

[0619] In one embodiment, improvement in substance / medication-induced anxiety disorder in patients who also have a 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.

[0620] somatic symptom disorder Somatic symptom disorder is a mental illness diagnosed when a patient is so preoccupied with physical symptoms, such as pain, weakness, or shortness of breath, that they cause significant distress and / or problems with functioning and / or interfere with daily life. The emotions and behaviors associated with the illness are excessive or disproportionate.

[0621] Health-related quality of life, both physical and mental, is often impaired. In severe somatic symptom disorders, the impairment is significant and, if persistent, can lead to debilitating conditions.

[0622] Patients with somatic symptom disorder may report sleep disturbances (eg, insomnia; patient dissatisfaction with the quality, timing, and quantity of sleep), which result in daytime distress and impaired functioning.

[0623] Sleep disorders can create a real vicious cycle between physical symptoms and sleep disturbances.

[0624] For example, insomnia correlates with the presence of physical symptoms, and the severity of insomnia correlates with the severity of physical symptoms, but this effect is not limited to insomnia, as alterations in the sleep-wake cycle may themselves be associated with the occurrence of physical symptoms.

[0625] Somatic symptom disorder can be assessed using the DSM-5 Level 2 Adult Somatic Symptom Scale. This scale consists of 15 somatic symptoms. Respondents are asked to rate the severity of their somatic symptoms over the past 7 days. Sleep disturbances are assessed by scoring "feeling tired or having low energy" and "having trouble sleeping." Scores range from "not bothering me at all (0 points)," "somewhat bothering me (1 points)," to "very bothering me (2 points)." Total scores can range from 0 to 30 points, with higher scores indicating greater somatic symptom severity. Cutoff scores of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0626] Additionally, sleep disturbances in individuals suffering from somatic symptom disorder can be assessed using the Pittsburgh Sleep Quality Index.

[0627] Functional brain connectivity analyses have revealed alterations within and / or between resting-state networks in patients with somatic symptom disorder compared with healthy controls. Alterations within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and somatomotor network (SMN) have been identified. Somatic symptom disorder may be associated with altered sensory-discriminative processing of somatic symptoms, which is influenced by emotional processing.

[0628] Treating patients with somatic symptom disorder and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of the somatic symptom disorder.

[0629] Reduction or elimination of sleep disturbances in patients with 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.

[0630] 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.

[0631] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0632] Improvement in sleep disturbance in patients with 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.

[0633] The improvement in sleep disturbance in patients with somatic symptom disorder, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0634] 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.

[0635] Reduction or elimination of sleep disturbances in patients with somatic symptom disorder is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0636] The reduction or elimination of sleep disturbances in patients with somatic symptom disorder, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0637] In one embodiment, reduction or elimination of sleep disturbances in patients with somatic symptom disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0638] As noted above, sleep disturbances are common in patients with somatic symptom disorder. Therefore, improving sleep disturbances will also lead to improvement in somatic symptom disorder. Because sleep disturbances also affect other aspects of somatic symptom disorder, the inventors concluded that improving sleep disturbances, specifically reducing or eliminating sleep loss, will further contribute to an overall improvement in somatic symptom disorder.

[0639] Improvement in somatic symptom symptoms in patients who also have sleep disturbances, 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.

[0640] The improvement in somatic symptom symptoms in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in somatic symptom symptoms in patients who also have a 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.

[0641] In one embodiment, improvement in somatic symptom symptoms in patients who also have a sleep disorder, as reflected by a reduction 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.

[0642] Obsessive-compulsive disorder and related disorders Obsessive-compulsive disorder (OCD) is a mental illness that causes recurring, unwanted thoughts or sensations (obsessions) or urges to do something over and over again (compulsions). Patients may have both obsessions and compulsions.

[0643] Patients with OCD may have a treatment-resistant form of the disorder.

[0644] 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.

[0645] Sleep disturbances are associated with treatment resistance in OCD, and therefore addressing these symptoms may enhance treatment outcomes.

[0646] 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, specifically the default mode network, has also been associated with sleep disturbances.

[0647] Treating patients with OCD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of the OCD.

[0648] Reduction or elimination of sleep disturbances in patients with 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.

[0649] 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 persists preferably for at least 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.

[0650] In one embodiment, reduction or elimination of sleep disturbances in a patient with 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.

[0651] 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.

[0652] The improvement in sleep disturbance in patients with OCD, as reflected by a reduction in CGI-S score, occurs within 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.

[0653] 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.

[0654] Reduction or elimination of sleep disturbances in patients with OCD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0655] The reduction or elimination of sleep disturbances in patients with OCD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0656] In one embodiment, reduction or elimination of sleep disturbances in patients with OCD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0657] As shown above, sleep disturbance is common in patients with OCD.Therefore, improving sleep disturbance will also lead to improvement of OCD.Since sleep disturbance also affects other aspects of OCD, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of OCD.

[0658] Improvement in OCD in patients who also have sleep disturbances, 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.

[0659] The improvement in OCD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in OCD in patients who also have a 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.

[0660] In one embodiment, improvement in OCD in patients who also have a 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.

[0661] Patients with body dysmorphic disorder (BDD) experience impaired functioning due to falsely perceived defects in their appearance, accompanied by distressing obsessions, ritualistic behaviors, and emotional distress.

[0662] Patients with BDD may have a treatment-resistant form of the disorder.

[0663] Sleep disturbances, specifically insomnia, are a common feature in patients with body dysmorphic disorder (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 greater impairment in daily functioning.

[0664] Functional magnetic resonance imaging (fMRI) in patients with BDD reveals alterations within and / or between specific brain regions located in the default mode network, dorsal attention network, and / or salience network. Alterations in functional connectivity in the affected networks, specifically the default mode network, have also been associated with sleep disturbances.

[0665] Treating patients with BDD and associated sleep disturbances, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances, thereby leading to improvement of BDD.

[0666] Reduction or elimination of sleep disturbances in patients 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.

[0667] The reduction or elimination of sleep disturbances in patients with BDD 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.

[0668] 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.

[0669] 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.

[0670] The improvement in sleep disturbance in patients with BDD, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0671] 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.

[0672] Reduction or elimination of sleep disturbances in patients with BDD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0673] The reduction or elimination of sleep disturbances in patients with BDD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 BDD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0674] In one embodiment, reduction or elimination of sleep disturbances in patients with BDD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0675] As shown above, sleep disturbance is common in patients with BDD.Therefore, improving sleep disturbance will also lead to improvement of BDD.Since sleep disturbance also affects other aspects of BDD, the inventors concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of BDD.

[0676] Improvement in BDD in patients who also have sleep disturbances, 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.

[0677] The improvement in BDD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BDD in patients who also have a 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.

[0678] In one embodiment, improvement in BDD in patients who also have a 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.

[0679] Post-traumatic stress disorder (PTSD) Post-traumatic stress disorder (PTSD) is a mental health condition that can develop based on a terrifying event that a patient experienced or witnessed. Symptoms can include flashbacks, nightmares, and severe anxiety, as well as irresistible thoughts about the event.

[0680] Patients with PTSD may have a treatment-resistant form of the disorder.

[0681] Sleep disorders have been linked to post-traumatic stress disorder (PTSD), with 70-90% of patients reporting at least one type of sleep disorder (insomnia, difficulty falling or staying asleep, or parasomnias such as nightmares).

[0682] Sleep disturbance, as difficulty falling asleep, difficulty staying asleep, or restless sleep, is one of six features of arousal abnormalities, at least two of which are required to diagnose PTSD based on DSM-5 criteria.

[0683] Sleep disturbances in PTSD can be assessed by self-administered questionnaires such as the PTSD Symptom Scale or the Trauma Screening Questionnaire (TSQ).

[0684] The PTSD Symptom Scale Self-Report is a 17-item self-report questionnaire for assessing symptoms of posttraumatic stress disorder. Sleep disturbances are assessed as the occurrence of bad dreams or nightmares or problems falling asleep or staying asleep. Respondents are asked to indicate how often they have experienced specific sleep disturbances over the past two weeks or another suitable recall period using a Likert-type scale ranging from 0 (never or only once) to 3 (almost always or five or more times per week). A score of 13 or higher indicates possible PTSD.

[0685] In the Trauma Screening Questionnaire, sleep (nightmares or difficulty falling asleep or staying asleep) is analyzed using two of 10 questions requiring a yes or no response. Six or more yes responses indicate a risk of having PTSD.

[0686] Resting-state functional magnetic resonance imaging analyses in patients with PTSD have revealed alterations within and / or between regions located in the default mode network and salience network.

[0687] Treating patients with PTSD and associated sleep disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of the PTSD.

[0688] Reduction or elimination of sleep disturbances in patients with 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.

[0689] The reduction or elimination of sleep disturbances in patients with PTSD 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.

[0690] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0691] 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.

[0692] The improvement in sleep disturbance in patients with PTSD, as reflected by a reduction in CGI-S score, occurs within 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.

[0693] 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.

[0694] Reduction or elimination of sleep disturbances in patients with PTSD is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] The reduction or elimination of sleep disturbances in patients with PTSD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 PTSD, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0696] In one embodiment, a reduction or elimination of sleep disturbances in a patient with PTSD, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0697] As shown above, sleep disturbance is an important aspect of PTSD.Therefore, improving sleep disturbance will also lead to the improvement of PTSD.Because sleep disturbance also affects other aspects of PTSD, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of PTSD.

[0698] Improvement in PTSD in patients who also have sleep disturbances, 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.

[0699] The improvement in PTSD in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in PTSD in patients who also have a 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.

[0700] In one embodiment, improvement in PTSD in patients who also have sleep disturbances, 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.

[0701] pain disorders Sleep disturbances occur in patients with pain and have been associated with chronic pain.

[0702] Chronic pain, also called persistent pain, is long-lasting pain that persists beyond the normal recovery period, for example after an injury or surgery, despite medication or treatment. Patients may also have chronic pain without an obvious cause, such as a history of injury or surgery.

[0703] The prevalence of insomnia, defined by dissatisfaction with sleep quantity or quality, difficulty falling asleep, difficulty staying asleep, and early morning awakening, in chronic pain populations is estimated to be 24–32%, nearly twice that of the general population.

[0704] When sleep disorders are defined by polysomnography, actigraphy, or self-report measures, the prevalence is estimated to be as high as 40–80% among chronic pain patients.

[0705] The relationship between sleep disorders and chronic pain is thought to be bidirectional, with insomnia later evolving into a standalone condition that requires direct treatment. Other conditions associated with sleep disorders, such as depression and anxiety, are also prevalent in chronic pain populations.

[0706] The relevance of sleep disturbance in chronic pain is reflected, for example, in the Brief Pain Inventory-Sf (BPI-sf), a nine-item self-administered questionnaire used to assess the severity of a patient's pain and its impact on their daily functioning. One of the items in the BPI-sf is sleep. The questionnaire assesses the disruption of sleep due to pain over the past 24 hours. Therefore, sleep disturbance is a relevant aspect of chronic pain.

[0707] Patients with chronic pain exhibit alterations in brain function and structure that are associated with the persistence of pain long after the initial nociceptive input has ceased. Resting-state functional magnetic resonance imaging reveals alterations in specific regions within and / or between the default mode network, somatomotor / sensorimotor network, and salience network.

[0708] Treating patients with chronic pain and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of chronic pain.

[0709] The reduction or elimination of sleep disturbances in patients with 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.

[0710] The reduction or elimination of sleep disturbances in patients with 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 with chronic pain persists preferably for at least 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.

[0711] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0712] Improvement in sleep disturbance in patients with 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.

[0713] The improvement in sleep disturbance in patients with chronic pain, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0714] In one embodiment, improvement in sleep disturbance in patients with 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.

[0715] Reduction or elimination of sleep disturbances in patients with chronic pain is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0716] The reduction or elimination of sleep disturbances in patients with chronic pain, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 chronic pain, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0717] In one embodiment, the reduction or elimination of sleep disturbances in patients with chronic pain, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0718] As shown above, sleep disturbance is an important aspect of the disease in patients with chronic pain. Therefore, improving sleep disturbance will also lead to the improvement of chronic pain. Because sleep disturbance also affects other aspects of chronic pain, the inventors concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of chronic pain.

[0719] Improvement in chronic pain in patients who also have a 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.

[0720] The improvement in chronic pain in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in chronic pain in patients who also have a 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.

[0721] In one embodiment, improvement in chronic pain in patients who also have a 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.

[0722] Fibromyalgia is a chronic disease characterized by widespread musculoskeletal pain throughout the body or in multiple areas, 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, clear thinking and memory (sometimes called "fibromyalgia fog"), sensitivity to light, noise, smells and temperature, or digestive problems such as bloating or constipation.

[0723] Research has shown that people with fibromyalgia are hypersensitive to pain and feel pain in situations where others do not.

[0724] Sleep disturbances and fatigue are common symptoms of fibromyalgia. Insomnia, non-restorative sleep, and fatigue are commonly used diagnostic indicators of fibromyalgia. Patients with fibromyalgia may also have restless legs syndrome.

[0725] Sleep disturbances in fibromyalgia can be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0726] 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.

[0727] The interplay of pain, fatigue, and poor quality sleep often interferes with a patient's ability to function at home or at work.

[0728] Conventional treatment for fibromyalgia is symptomatic.

[0729] Brain imaging and other studies have revealed evidence of altered signaling in the neural pathways that transmit and receive pain in patients with fibromyalgia. These changes may also contribute to the fatigue, sleep disturbances, and cognitive problems experienced by many people with the disease.

[0730] Resting-state functional magnetic resonance imaging in patients with fibromyalgia has shown altered 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 pain.

[0731] Treating patients with fibromyalgia and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of fibromyalgia.

[0732] The reduction or elimination of sleep disturbances in patients with fibromyalgia 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] The reduction or elimination of sleep disturbances in a patient with 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 with fibromyalgia persists preferably for at least 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, the reduction or elimination of sleep disturbances in a patient with 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.

[0735] 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.

[0736] The improvement in sleep disturbance in patients with fibromyalgia, as reflected by a reduction in CGI-S score, occurs within 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.

[0737] In one embodiment, improvement in sleep disturbance in patients 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.

[0738] Reduction or elimination of sleep disturbances in patients with fibromyalgia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0739] The reduction or elimination of sleep disturbances in patients with fibromyalgia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 fibromyalgia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0740] In one embodiment, the reduction or elimination of sleep disturbances in a patient with fibromyalgia, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0741] As shown above, sleep disturbance is one of the most common complaints of fibromyalgia patients.Therefore, improving sleep disturbance will also lead to the improvement of fibromyalgia.Because sleep disturbance also affects other aspects of fibromyalgia, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of fibromyalgia.

[0742] Improvement in fibromyalgia in patients who also have sleep disturbances, 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.

[0743] The improvement in fibromyalgia in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in fibromyalgia in patients who also have a 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.

[0744] In one embodiment, improvement in fibromyalgia in patients who also have sleep disturbances, 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.

[0745] A migraine is a headache that usually occurs on one side of the head and can cause severe throbbing or pulsating pain. Migraines are often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last from several hours to several days, and the pain can be so severe that it can interfere with daily life.

[0746] Some patients may experience a symptom called an "aura" before or along with their headache, which may include visual abnormalities such as flashing lights or blind spots, or tingling on one side of the face or in the arms or legs, and other disturbances such as difficulty speaking.

[0747] The most common sleep disorder in migraine sufferers is insomnia. This includes difficulty falling asleep or staying asleep, early morning awakenings, and unrestorative sleep. Insomnia impairs daytime functioning, resulting in fatigue, decreased attention and concentration, and loss of motivation.

[0748] The presence of sleep disorders is associated with more frequent and severe migraines.

[0749] The Pittsburgh Sleep Quality Index (PSQI) is a common self-report sleep questionnaire used to assess sleep quality over the past month and has been used in many studies to assess poor sleep quality in migraine patients.

[0750] Headache disorders are associated with atypical functional connectivity in regions involved in pain processing, as well as within and / or between multiple core resting-state networks, including the salience network and default mode network.

[0751] Resting-state network analyses have shown differences in migraine patients compared with healthy controls, and studies during migraine attacks have revealed significant abnormalities in networks involved in mediating cognitive, attentional, somatosensory, and affective components of pain.

[0752] Treating patients with migraine and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, which in turn leads to improvement of the migraine.

[0753] The reduction or elimination of sleep disturbances in patients with 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.

[0754] The reduction or elimination of sleep disturbances in a patient with migraine 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.

[0755] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0756] Improvement in sleep disturbance in patients with migraine, as reflected by a reduction 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.

[0757] The improvement in sleep disturbance in patients with migraine, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0758] In one embodiment, improvement in sleep disturbance in patients with migraine, as reflected by a reduction 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.

[0759] Reduction or elimination of sleep disturbances in patients with migraine is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0760] The reduction or elimination of sleep disturbances in patients with migraine, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 migraine, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0761] As shown above, sleep disturbance is one of the most common complaints of migraine sufferers.Therefore, improving sleep disturbance will also lead to the improvement of migraine.Since sleep disturbance also affects other aspects of migraine, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of migraine.

[0762] In one embodiment, the reduction or elimination of sleep disturbances in patients with migraine, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0763] Improvement in migraine headaches in patients who also have sleep disturbances, as reflected by a reduction 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.

[0764] The improvement in migraine headaches in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in migraine headaches in patients who also have a 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.

[0765] In one embodiment, improvement in migraine headaches in patients who also have a sleep disorder, as reflected by a reduction 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.

[0766] Mental and behavioral disorders due to drug use Sleep disorders occur in patients with certain mental and behavioral disorders due to the use of psychoactive substances.

[0767] Substance use disorders (SUDs) are mental health disorders that affect a person's behavior and cause an inability to control their use of substances such as legal or illegal drugs, alcohol, or medicines. Symptoms range from moderate to severe, with addiction being the most severe form of SUD.

[0768] Resting-state functional connectivity (rsFC) has been reported to be altered not only in patients with sleep disorders but also in patients with substance use disorders. Specifically, 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.

[0769] Substance / drug-related sleep disorders are characterized by severe alterations in sleep patterns that require independent clinical attention and are judged to be caused primarily by the pharmacological effects of a substance (e.g., drug of abuse, medication, or exposure to a toxin).

[0770] Sleep disorders can result from intoxication and / or withdrawal from alcohol, caffeine, cannabis, opioids, sedatives (hypnotics or anxiolytics), tobacco, stimulants (such as cocaine), or other substances.

[0771] Certain medications, such as adrenergic agonists / antagonists, dopaminergic agonists / antagonists, cholinergic agonists / antagonists, serotonergic agonists / antagonists, antihistamines, or corticosteroids, may also cause sleep disturbances.

[0772] Depending on the substance used, one of four types of sleep disorders has been reported: insomnia and daytime sleepiness are the most common, while parasomnia is less common. A mixed type is observed when multiple sleep disorder-related symptoms are present simultaneously, with no symptom predominating.

[0773] As the withdrawal / abstinence state from a particular substance continues, sleep disorders may develop as early as 4 weeks after cessation of substance use and may have characteristics not seen in other sleep disorders (e.g., atypical age of onset or course).

[0774] The significant impact of sleep disturbances in substance use disorders has been reflected in 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." Scores range from 0 to 23, with lower scores indicating better sleep and higher scores indicating worse sleep.

[0775] Treating patients with substance use disorders and associated sleep disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of the substance use disorder.

[0776] Reduction or elimination of sleep disturbances in patients with substance use disorders 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.

[0777] 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.

[0778] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0779] 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.

[0780] The improvement in sleep disturbance in patients with substance use disorders, as reflected by a reduction in CGI-S score, occurs within 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.

[0781] In one embodiment, improvement in sleep disturbance in patients with a substance use disorder, as reflected by a reduction 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.

[0782] Reduction or elimination of sleep disturbances in patients with substance use disorders is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0783] The reduction or resolution of sleep disturbances in patients with substance use disorders, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of sleep disturbances in patients with substance use disorders, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0784] 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 points 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.

[0785] As shown above, sleep disturbance is an important aspect of the disease in patients with substance use disorder.Therefore, improving sleep disturbance will also lead to improvement of substance use disorder.Since sleep disturbance also affects other aspects of substance use disorder, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will further contribute to the overall improvement of substance use disorder.

[0786] Improvement in substance use disorder in patients who also have a 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.

[0787] The improvement in substance use disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in substance use disorder in patients who also have a 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.

[0788] In one embodiment, improvement in substance use disorder in patients who also have a 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.

[0789] Psychotic disorders Psychotic disorders are severe mental disorders that cause abnormal thinking and perceptions. They are characterized by marked impairments in reality testing and altered behavior, manifested by persistent delusions, persistent hallucinations, disorganized thinking (usually manifested as disorganized speech), markedly disorganized behavior, and positive symptoms such as experiencing passivity and control, negative symptoms such as blunted affect or decreased motivation, and psychomotor impairments.

[0790] Patients with psychotic disorders may have treatment-resistant forms of the disorder.

[0791] 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 comorbid conditions. Patients often have not just one isolated sleep disorder, but multiple disorders. Most of these sleep disorders are rated as severe in terms of chronicity, frequency, and distress or impairment.

[0792] Because of the significant impact that sleep disturbances can have on the course of psychotic disorders, sleep quality in patients with psychotic disorders is assessed with rating scales commonly used to diagnose or assess sleep disorders, such as the PSQI or Sleep50.

[0793] Functional magnetic resonance imaging of resting-state networks in the brains of patients with psychosis reveals significant alterations within and / or between specific regions of the central executive network, default mode network, and salience network. Alterations in resting-state networks may also be observed in patient populations at risk for psychosis.

[0794] Treating patients with psychotic disorders and associated sleep disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of the psychotic disorder.

[0795] The reduction or elimination of sleep disturbances in patients with 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.

[0796] The reduction or elimination of the sleep disturbance in the patient with 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 the sleep disturbance in the patient with 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.

[0797] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0798] Improvement in sleep disturbance 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.

[0799] The improvement in sleep disturbance in patients with a psychotic disorder, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0800] In one embodiment, improvement in sleep disturbance in patients with 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.

[0801] Reduction or resolution of sleep disturbances in patients with a psychotic disorder is reflected by improvement in the Pittsburgh Sleep Quality Index (PSQI) global score on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period is from the time the acute psychedelic experience following the last administration subsided to the time of assessment.

[0802] The reduction or resolution of sleep disturbances in patients with a psychotic disorder, as reflected by an improvement in the PSQI global score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period is from the time the acute psychedelic experience following the last administration subsides to the time of assessment. The reduction or resolution of sleep disturbances in patients with a psychotic disorder, as reflected by an improvement in the score on the PSQI sleep disturbance component, preferably persists for at least 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.

[0803] In one embodiment, reduction or elimination of sleep disturbances in a patient with a psychotic disorder, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0804] As shown above, the occurrence of various forms of sleep disorders is an important disease aspect in patients with psychotic disorders.Therefore, the improvement of sleep disorders will also lead to the improvement of psychotic disorders.Because sleep disorders also affect other aspects of psychotic disorders, the inventors conclude that the improvement of sleep disorders will further contribute to the overall improvement of psychotic disorders.

[0805] Improvement in psychotic disorder in patients who also have a 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.

[0806] The improvement in the psychotic disorder in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the psychotic disorder in patients who also have a 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.

[0807] In one embodiment, improvement in the psychotic disorder in patients who also have a 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.

[0808] Schizophrenia is a severe mental illness characterized by disturbances in multiple mental modalities, including thought, perception, self-experience, cognition, motivation, emotion, and behavior. Psychomotor disturbances, including catatonia, may also be present.

[0809] Patients with schizophrenia may have a treatment-resistant form of the disorder.

[0810] Abnormalities in resting-state functional connectivity, particularly within and / or between the default mode network, frontoparietal network, and salience network, have been reported in patients with schizophrenia.Several studies have found an association between sleep disturbances and symptom severity in individuals at high risk for psychosis and those diagnosed with schizophrenia.

[0811] Psychotic experiences often interfere with good quality sleep, and the resulting sleep problems cause daytime fatigue, reducing the ability of people with schizophrenia to cope with their psychotic symptoms.

[0812] The sleep disorder most strongly associated with schizophrenia is insomnia.

[0813] Patients with schizophrenia who experience comorbid sleep disorders tend to have a lower quality of life as assessed by physical health, psychological well-being, social relationships, and environmental factors. Patients with schizophrenia who experience sleep disorders also report significantly lower satisfaction with life, and the presence of insomnia and comorbid nightmares is associated with an increased risk of suicide attempts.

[0814] Sleep disturbances are an essential aspect in patients with schizophrenia and can be assessed with common sleep scales such as the Pittsburgh Sleep Quality Index (PSQI).

[0815] Treating patients with schizophrenia and associated sleep disorders, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disorders, thereby leading to improvement of schizophrenia.

[0816] The reduction or elimination of sleep disturbances in patients with 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.

[0817] The reduction or elimination of sleep disturbances in a patient with 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 with schizophrenia preferably persists for at least 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.

[0818] In one embodiment, the reduction or elimination of sleep disturbances in a patient with 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.

[0819] 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.

[0820] The improvement in sleep disturbance in patients with schizophrenia, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0821] In one embodiment, improvement in sleep disturbance in patients with schizophrenia, as reflected by a reduction 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.

[0822] Reduction or elimination of sleep disturbances in patients with schizophrenia is reflected by an improvement in the Pittsburgh Sleep Quality Index (PSQI) global score, specifically a reduction to 5 points or less, on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0823] The reduction or elimination of sleep disturbances in a patient with schizophrenia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points or less, 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 schizophrenia, as reflected by an improvement in the PSQI global score, particularly a reduction to 5 points 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.

[0824] In one embodiment, the reduction or elimination of sleep disturbances in a patient with schizophrenia, as reflected by an improvement in PSQI score, particularly a reduction to 5 points 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.

[0825] As mentioned above, sleep disorders are central to the clinical picture of schizophrenia. Therefore, improving sleep disorders will also lead to improvement of schizophrenia. Because sleep disorders also affect other aspects of schizophrenia, the inventors concluded that improving sleep disorders will further contribute to the overall improvement of schizophrenia.

[0826] Improvement in schizophrenia in patients who also have sleep disturbances, 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.

[0827] The improvement in schizophrenia in patients who also have a sleep disorder, as reflected by a reduction in CGI-S score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in schizophrenia in patients who also have a 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.

[0828] In one embodiment, improvement in schizophrenia in patients who also have a 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 ...

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for the treatment of sleep disorders in patients with sleep disorders.

2. The pharmaceutical composition according to claim 1, wherein the sleep disorder is insomnia.

3. The pharmaceutical composition according to claim 1 or 2, wherein the sleep disorder is a sudden onset sleep disorder.

4. The pharmaceutical composition according to claim 1, wherein the patient has a mental illness or neurological disorder accompanied by the sleep disorder.

5. The pharmaceutical composition according to claim 4, wherein the patient has a treatment-resistant form of the disorder.

6. The pharmaceutical composition according to claim 1, wherein the patient has a disease characterized by a depressive episode accompanied by a sleep disorder.

7. The pharmaceutical composition according to claim 6, wherein the patient currently has a major depressive episode.

8. The pharmaceutical composition according to claim 1, wherein the patient has major depressive disorder (MDD) accompanied by the sleep disorder.

9. The pharmaceutical composition according to claim 8, wherein the patient has a treatment-resistant form of the disorder.

10. The pharmaceutical composition according to claim 1 or 2, wherein the treatment reduces or eliminates the sleep disorder.

11. The pharmaceutical composition according to claim 10, wherein the reduction or elimination of the sleep disorder is observed at least 1 day (e.g., about 24 hours), at least 7 days, at least 14 days, and / or at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition according to claim 4, wherein the treatment results in improvement of the diagnosed disease in a patient who also has a sleep disorder.

13. The pharmaceutical composition according to claim 12, wherein improvement of the diagnosed disorder in patients with sleep disorders, reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, is observed approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least 1 day (e.g., approximately 24 hours), at least 7 days, at least 14 days, and / or at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

15. The pharmaceutical composition according to claim 1 or 2, wherein a dose of 5-MeO-DMT in an amount of approximately 4 mg to approximately 20 mg is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered.

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

17. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations.

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

19. The pharmaceutical composition according to claim 17, wherein the patient is administered subsequent doses unless he or she experiences a supreme psychedelic experience.

20. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT is administered in a dose of approximately 2 mg to approximately 8 mg in a first dose, then increased to a dose of approximately 8 mg to approximately 14 mg in a second dose unless the patient has already experienced a peak psychedelic experience or the attending physician determines that further dose increases are inappropriate based on observed side effects, then increased to a dose of approximately 14 mg to approximately 20 mg in a third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered.

21. The pharmaceutical composition according to claim 20, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered.

22. The pharmaceutical composition according to claim 17, wherein the interval between two doses is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably 1 to 2 hours.

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

24. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by inhalation, or by nasal administration, buccal administration, or sublingual administration.

25. The pharmaceutical composition according to claim 1 or 2, wherein the sleep disorder is measured using the Pittsburgh Sleep Quality Index.

26. The pharmaceutical composition according to claim 1 or 2, wherein the treatment results in improvement in at least one of cognitive impairment, anxiety, psychomotor developmental delay, social withdrawal, emotional withdrawal, and negative thinking.