5-MEO-DMT for treatment of sleep disorders

Abstract

The present invention relates to 5-methoxyl-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a patient suffering from a sleep disorder.

Description

Technical Field

[0001] The present invention relates to improved methods for treating sleep disorders, particularly sleep disorders in patients suffering from psychiatric or neurological disorders, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, for example, 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 (OCD) and related disorders, for example, obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); posttraumatic stress disorder (PTSD); pain disorders, for example, chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from the use of psychoactive substances, for example, substance use disorders (SUD); psychotic disorders, for example, schizophrenia; Huntington's disease (HD) Disease); Parkinson's Disease; Dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia, Lewy body dementia, 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 associated with HIV, traumatic brain injury, or COVID sequelae.

[0002] The treatment comprises 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 Art

[0003] Sleep disturbances (somnias) are conditions that affect the quality, timing, or duration of sleep. They can affect a person's ability to function normally while awake.

[0004] Sleep disturbances may be idiopathic or may occur in the context of a medical condition, such as a psychiatric or neurological disorder. In fact, several psychiatric and neurological disorders are known to be associated with sleep disturbances.

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

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

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

[0008] It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that have better safety and / or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that are more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that are associated with higher rates of patient compliance (including higher rates of treatment initiation) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that may 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 patients suffering from sleep disorders, particularly insomnia, excessive sleep and / or circadian rhythm disorders.

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

[0011] Sleep disturbances may be idiopathic or may occur in patients with psychiatric or neurological disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type 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); Post-traumatic stress disorder (PTSD); pain disorders such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia, Lewy body dementia, 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 mental or neurological disorders associated with HIV, traumatic brain injury, or COVID sequelae.

[0012] The present invention also provides dosage ranges and administration regimens that can be used to treat sleep disorders. DETAILED DESCRIPTION

[0013] definition

[0014] As used in the context of the present invention, unless otherwise indicated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, wherein the acid may be selected, for example, from acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated based on the weight of the free base, assuming equimolar amounts are used.

[0015] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional in accordance with generally accepted medical practice as suffering from a sleep disorder or who has been diagnosed by a licensed professional in accordance with generally accepted medical practice as suffering from a psychiatric disorder or a neurological disorder associated with a sleep disorder. In the latter case, an assessment of the sleep disorder may or may not be part of the diagnosis.

[0016] For example, the diagnosis of mental disorder or nervous system disorder can be carried out according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) issued by the American Psychiatric Association. In some cases, as will be apparent from the discussion of specific circumstances hereinafter, it is possible to modify or supplement criteria to better define a patient or patient group that particularly benefits from treatment according to the present invention. In any case, diagnosis will be carried out by a doctor or psychologist. It is not enough for a human experimenter to believe that he or she suffers from the disorder.

[0017] As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition or disorder, and include the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition or disorder.

[0018] "Treatment of sleep disorders" shall include the management and care of a patient for the purpose of combating sleep disorders, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of sleep disorders or to eliminate sleep disorders. Sleep disorders may be idiopathic or may be associated with psychiatric or neurological disorders.

[0019] The patient may have a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. In particular, the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses is medication; for example, the patient has not adequately improved after at least two adequate courses of medication. In particular, at least two prior courses of treatment were administered during the current episode of the disease, for example, if the patient has a disorder characterized by a depressive episode, during the current depressive episode.

[0020] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by the researcher, physician, or other clinician, including alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0021] "Clinical response" includes, but is not limited to, improvement on rating scales that assess (i) sleep disturbance or aspects of sleep disturbance and / or (ii) a psychiatric or neurological disorder or aspects of such a disorder.

[0022] The severity of the disorder and changes in severity can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and treatment efficacy.

[0023] The CGI rating scale was developed to provide a brief, independent assessment of the clinician's perception of a patient's global functioning before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0024] The CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is this patient currently?” Rated on a seven-point scale: 1 = normal, not ill at all; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat ill; 6 = severely ill; and 7 = the patient with the most severe illness.

[0025] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0026] Alternatively, the CGI-Improvement (CGI-I) can be used to assess treatment success, which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, there is only one question, rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), the patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

[0027] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI). It consists of one item based on the CGI and adapted for the patient. It can measure either disease severity (PGI-S) or disease improvement (PGI-I).

[0028] Individual items as well as subcombinations of individual items of the scales as described herein can be used to assess specific disease aspects.

[0029] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "applying") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into the patient's body via any route. Preferably, the active compound is administered by inhalation, nasal administration, buccal administration or sublingual administration.

[0030] As used in the context of the present invention, unless otherwise indicated, the terms "dose," "dosage," and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined sequence of one or more separate administrations.

[0031] As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and tiny suspended solid and / or liquid particles. The term "degradation product" refers to a compound produced by chemical modification of the active agent due to a chemical reaction that occurs during the formation of the aerosol. Such reactions include, but are not limited to, oxidation. When describing the percentage of "degradation product" in the context of the present invention, this refers to the amount of active agent degradation product present in the sample divided by the amount of active agent plus active agent degradation product present in the sample multiplied by 100%, that is, (the sum of the amounts of all active agent degradation products present in the sample) / ((the amount of active agent present in the sample)+(the sum of the amounts of all active agent degradation products present in the sample)) x 100%. As used herein, the term "impurity" refers to an unwanted compound that contaminates the active agent sample. Impurities may be contained in the starting material before the aerosol is formed, or they may be degradation products.

[0032] The term "purity" refers to 100% minus the percentage of all active agent degradation products present and 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%.

[0033] The term "mass median aerodynamic diameter" (MMAD) is the diameter such that 50% of the particles present in the aerosol are larger than the calculated diameter and 50% of the particles are smaller than the calculated diameter. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the mass of active agent aerosolized per unit aerosolization time.

[0034] Sleep disorders

[0035] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing sleep depth. Non-REM and REM sleep alternate during the four to five cycles of normal human sleep each night. During the early part of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, especially in the first sleep cycle. As the night progresses, non-REM sleep becomes lighter, and more of each cycle is allocated to REM sleep.

[0036] Normal, healthy sleep consists of the different stages described above, which proceed in a continuous, strictly controlled sequence throughout the night.

[0037] Disruptions in this tight control can lead to sleep disturbances.

[0038] Sleep disturbances are conditions that affect the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition (e.g., a psychiatric or neurological disorder). They can affect a person's ability to function normally while awake.

[0039] Common forms of sleep disturbances include disorders of falling asleep and maintaining sleep (insomnias), disorders of excessive sleepiness (hypersomnias), disorders of the sleep-wake schedule (circadian rhythm disorders), disorders related to sleep, sleep stages, or partial arousals (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0040] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have trouble falling asleep; wake up frequently during the night and have trouble falling asleep again; wake up too early in the morning; have poor sleep quality; and / or have at least one daytime problem due to poor sleep quality, such as fatigue, sleepiness, mood problems, difficulty concentrating, or accidents while working or driving.

[0041] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomniacs. The transition from sleep to wakefulness is difficult. Individuals who experience sleep drunkenness report feeling confused, disoriented, sluggish, and drifting back to sleep upon awakening.

[0042] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances due to alterations in an individual's internal circadian rhythm or due to a mismatch between their circadian rhythm and their desired or required work or social schedule. This missynchrony may be temporary or persistent. The resulting clinical presentation combines symptoms of insomnia and hypersomnia. Sleep duration is often shortened and disrupted, performance during desired wakefulness is impaired, and restoration of a normal sleep schedule is temporarily prevented.

[0043] Parasomnias refer to various forms of sleep disorders characterized by unusual behavioral or physiological activity (such as sleepwalking or nightmares) experienced before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in the characteristics, severity, and frequency of parasomnias. Parasomnias can impair sleep quality.

[0044] 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 control center in the brain. One form of sleep-related breathing disorder is central sleep apnea. This occurs, for example, when the brain stops sending signals to control breathing, depending on an underlying health condition. Central sleep apnea has potentially serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow leads to intermittent periods of hypoxia, which can fragment sleep due to micro-arousals or awakenings. The consequence can be excessive daytime sleepiness.

[0045] In sleep-related movement disorders, repetitive, relatively simple, often stereotyped movements disrupt sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0046] Insufficient sleep quantity or quality can lead to personality changes and may not only exacerbate existing mental illnesses but also contribute to their development. Disrupted sleep can also interfere with cognitive function and lead to memory impairment. Sleep-deprived individuals may experience difficulty making decisions, irritability, poor performance, and potentially slower reaction times. Insufficient sleep can also negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0047] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatment. If unsuccessful, treatment may involve medication or psychotherapy.

[0048] Available treatments are not successful in all patients, may be associated with side effects and / or require long-term treatment to achieve a relevant therapeutic effect.

[0049] In patients with sleep disturbances associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorder do not necessarily improve the sleep disturbance.

[0050] For example, sleep disturbances are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily result in an improvement in the accompanying sleep disturbances. Although most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while other antidepressants may cause impaired sleep.

[0051] Measuring sleep disturbances

[0052] Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of wakefulness throughout the night. Quantitative indicators can be measured using objective methods, including polysomnography, actigraphy, and determination of sleep latency, or by self-report measurements (questionnaires).

[0053] Polysomnography is a technique that involves monitoring patients throughout the night in a specialist clinic. Various functions are measured throughout the night, including eye movements, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body posture and movement, snoring, and heart rate.

[0054] Another quantitative measure is actigraphy. Actigraphy sensors are worn to measure motor activity, which is continuously recorded and used to assess sleep-wake cycles. This technology allows patients to continue their normal lives while recording the required data in a natural sleep environment.

[0055] Sleep latency can be measured using the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep after multiple test naps. An average sleep latency of approximately 10 minutes is considered normal; less than eight minutes indicates sleep disturbance (excessive daytime sleepiness). Accompanying brain activity analysis can help further diagnose sleep disorders.

[0056] The sleep assessment questionnaire captures ratings of components of sleep quality, such as perception of sleep depth, difficulty waking, and rest after sleep, as well as other factors that may influence sleep quality, such as comorbidities and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep complaints can often persist despite normal quantitative sleep measures.

[0057] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful in tracking patient progress.

[0058] A variety of sleep quality indices are known. The following indices include examples of questionnaires for assessing general sleep and examples of questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias, respectively. However, the present invention is not limited to the use of a particular index or questionnaire.

[0059] Some questionnaires rely on a recall period (recall window) of several days or even weeks. While this may be suitable for diagnosing sleep disorders, it is not always suitable for assessing the effectiveness of treatment, especially the effects that occur quickly after treatment. For several questionnaires, the recall period can be modified so that the scores obtained reflect a period of time after treatment. In particular, this paper discusses questionnaires for assessing the effect of treatment on sleep in patients suffering from specific conditions, which rely on a recall period that starts no earlier than the time when the acute psychedelic experience has subsided after the last administration. In order to meet the criteria, the normally applied recall period is modified if necessary.

[0060] For example, the Sleep-50 questionnaire can be used to assess general sleep quality.

[0061] 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 disorders and discomforts related to sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorders, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily functioning. For each item, respondents are given a scale from 1 ("not at all") to 4 ("very much") and are asked to indicate the extent to which the statement matches their experience in the last month or another appropriate recall window.

[0062] To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the respondent must also achieve a cutoff point of at least 3 or 4 ("quite a bit" or "very much," respectively) on the subscale that assesses the impact of sleep discomfort on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. BehaV Sleep Med. 2005;3(4):227-46).

[0063] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0064] A commonly used questionnaire to assess sleep disturbances is the Pittsburgh Sleep Quality Index. Other tools include the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System. )Sleep disorders.

[0065] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-assessment questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

[0066] Nineteen self-rated questions assess various factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. These 19 items are divided into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

[0067] Each component is scored on a scale of 0 to 3. Higher scores indicate more severe sleep disturbances. Detailed scoring instructions for the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213.

[0068] The seven component scores are then summed to create an overall score, ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A global score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A global score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0069] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

[0070] The Insomnia Severity Index (ISI) is a short questionnaire that addresses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how significant the respondent feels their insomnia is compared to other people, and the level of overall distress caused by sleep problems. Individual responses can be scored from 0 (=none) to 4 (=very); a higher total score corresponds to more severe insomnia. A total score of 0-7 means "no clinically significant insomnia", 8-14 means "subthreshold insomnia", 15-21 means "clinical insomnia (moderate severity)", and 22-28 means "clinical insomnia (severe)" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012,.); the recall window is two weeks. Another appropriate recall window may also be used.

[0071] Treatment success is indicated by (i) a decrease in the score, for example a decrease of >7 points, particularly >8 points; and preferably (ii) a decrease in the score to below the cutoff for clinically significant insomnia.

[0072] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ assesses restlessness / agitation, mental overactivity, consequences of insomnia, and inadequate preparation for sleep, with a particular focus on beliefs about the root causes of sleep problems. Respondents use a five-point scale to indicate how often certain statements about insomnia represent their experience. 1 means "never true," while 5 means "often true." Higher scores indicate more dysfunctional beliefs about the causes and associated factors of insomnia (A. Shahid et al., supra).

[0073] A decrease in the score indicates successful treatment.

[0074] Patient-Reported Outcomes Information System The Sleep Disturbance Tool is a general method for assessing sleep disturbances. The tool has a long form and four different short forms (e.g., 4, 6, and 8 items) and assesses self-reported sleep quality, perception of sleep depth, and any perceived difficulties with falling and staying asleep over a 7-day period.

[0075] Each item in the measure is rated on a 5-point scale. The raw scores for each item are summed to obtain a total raw score. The total raw score is then converted to a standardized T score using a conversion table.

[0076] Treatment success was indicated by a decrease in T score.

[0077] Excessive sleepiness or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0078] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stopped in traffic. Respondents rate their likelihood of falling asleep using a scale of 0-3 (0 meaning "never doze off" and 3 meaning "very likely doze off"). Scores range from 0-24; the higher the score, the greater the severity of daytime sleepiness. A cutoff score of 10 indicates that daytime sleepiness may occur at a clinical level (A. Shahid et al., supra).

[0079] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 10 or less.

[0080] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses the degree of sleepiness at a particular moment. The scale consists of only one item, asking the respondent to select one of seven statements that best represents their current perceived level of sleepiness. The degree of sleepiness is assessed using a scale ranging from 1 (=feeling active and energized; alert; wide awake) to 7 (=almost in a trance; falling asleep quickly; unable to stay awake) (A. Shahid et al., supra).

[0081] A decrease in the score indicates successful treatment.

[0082] Parasomnias can be assessed using the Paris Arousal Disorders Severity Scale (PADSS).

[0083] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnias, assesses their frequency, and includes an evaluation of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0084] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0085] A commonly used questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period can also be selected.

[0086] A decrease in the score indicates successful treatment.

[0087] A commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire requires respondents to use a Likert-type rating method to indicate how severe the impact of this disorder on them has been in the past week. The questions can be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep problems, daily function disturbances, and resulting mood changes). Each of the ten questions requires respondents to rate their RLS experience on a scale of 0 to 4, with 4 representing the most severe and most frequent symptoms and 0 representing the least symptoms. The total score range can be 0 to 40. As a short scale with excellent psychometric quality, the tool is suitable for a variety of research and clinical purposes, including screening and evaluating treatment outcomes. (A. Shahid et al., supra).

[0088] The response to treatment can be assessed by a decrease in the score.

[0089] Scales for assessing mental and neurological disorders

[0090] A variety of scales have been proposed to assess the severity of mental or neurological disorders. Such scales are based on tests that can be self-administered or administered by a clinician.

[0091] Scales for assessing mental or neurological disorders that can be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring mental or neurological disorders as discussed in more detail below.

[0092] Treatment outcomes are assessed using one or more indices or scales at one or more time points after completion of the treatment course.

[0093] The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2 to 3 hours after the last administration. Early assessment can typically be performed, for example, about 2 hours or about 3 hours after the last administration.

[0094] However, assessment of effects on sleep disruption or on psychiatric or neurologic disorders related to effects on sleep disruption can be performed as early as the day after treatment (ie, day 1), allowing the treated patient an opportunity to get at least one night of sleep.

[0095] Thus, an assessment on day 1 or day 1 means an assessment on the second day after administration. The assessment will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. The assessment may be performed after about 24 hours.

[0096] Assessment on day 7 or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

[0097] When the clinical response is assessed at an early time point (e.g., 2 hours) after drug administration, for example, when one of the scales is used to assess the severity of a psychiatric or neurological disorder, reasonable modifications can be made to such endpoints based on endpoints developed for a longer recall period (e.g., MADRS is typically 7 days) (e.g., changing the MADRS recall period to 2 hours and carrying over the sleep items recorded at the baseline before drug administration). Unless a recall period is specifically specified, the same applies to any other scale used herein to assess the effect of treatment on a psychiatric or neurological disorder.

[0098] The considerations outlined apply to early time points because, on the one hand, in order to assess clinical response, the influence of the patient's pre-treatment status on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0099] At a later time point, such as on day 1 or later, all items of the relevant scale used to assess clinical response can generally be assessed using an appropriate recall period (if needed) so that no pre-treatment scores need to be carried forward.

[0100] Resting-state networking and sleep disturbances

[0101] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0102] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of the spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0103] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0104] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0105] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0106] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0107] Alterations in resting-state networks have been found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0108] A key network involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during tasks and activated during rest. It participates in a variety of cognitive processes, including higher-order cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given its importance to sleep physiology, alterations in DMN activity are particularly relevant to sleep disorders.

[0109] Impairments in resting-state networks can also be found in psychiatric or neurological disorders, particularly disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I and bipolar II; 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); and post-traumatic stress disorder. post-traumatic stress disorder (PTSD); pain disorders such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders due to psychoactive substance use, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia, Lewy body dementia, 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 mental or neurological disorders associated with HIV, traumatic brain injury, or COVID-19.

[0110] Resting-state networks involved in sleep disruption can also be affected by psychiatric or neurological disorders caused by certain medical health conditions.

[0111] In patients with insomnia, functional connectivity impairments have been observed within the default mode network (DMN) and the salience network, which are associated with the detection and integration of emotional and sensory stimuli. Studies have shown that these networks contain key areas for integrating emotional and physical states, and that functional connectivity impairments within and / or between these networks and other brain regions may contribute to patients' perceived alertness, subjective distress, and poor sleep continuity.

[0112] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, different DMN hubs (precuneus and medial prefrontal cortex) show significant changes, and functional connectivity within the DMN is correlated with self-reported sleepiness severity.

[0113] A study examining the differences between night-shift nurses and day-shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, which is involved in sleep regulation and cognitive functions such as responsiveness and alertness. Furthermore, functional connectivity of the DMN differs fundamentally between early and late circadian phenotypes. Like other forms of sleep disturbance, circadian rhythm disturbances can lead to changes in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disturbances.

[0114] Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders representing non-REM parasomnias.

[0115] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information, as well as monitoring movement. It is a subregion of the DMN. Therefore, the default mode network is affected in patients with parasomnias.

[0116] Resting-state fMRI studies of patients with sleep-related breathing disorders, such as central sleep apnea, have demonstrated profound global and regional connectivity deficits, particularly in the default mode network (DMN) and in regions involved in arousal and sensorimotor systems.

[0117] Sleep-related movement disorders, such as periodic limb movements during sleep, were reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Furthermore, activity was observed in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem.

[0118] In many cases, abnormal functional connectivity of resting-state networks involved in sleep disturbances is also involved in the aforementioned disorders. Therefore, according to the present invention, affecting those networks by the therapy according to the present invention will lead to an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric or neurological disorder, also to an improvement in said disorder.

[0119] Active agent

[0120] The above discussion shows that sleep disturbances themselves carry a significant disease burden and should be treated appropriately.

[0121] The inventors believe that carefully selected hallucinogens may lead to treatment that improves important aspects of sleep disorders and may result in an overall improvement of the condition.

[0122] A group of hallucinogens comprises compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often referred to as "psychedelics," emphasizing their primary ability to induce qualitatively altered states of consciousness, such as euphoria, trance, time and space, mental experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

[0123] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamines divided into two subsets, the ergoline and the tryptamines, the latter being derived from tryptamine.

[0124] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-related receptors.

[0125] Recently published studies on the use of serotonergic psychedelics, such as LSD, psilocybin, and DMT (using the shamanic infusion ayahuasca, which contains DMT), in certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients with depressive symptoms, and this may hinder their clinical use.

[0126] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported a case in which a patient experienced a manic episode after taking LSD or an LSD analog. The patient experienced symptoms of acute LSD intoxication, which resolved, but a typical psychotic manic episode developed approximately 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4): 1-3) reported a manic episode after self-reported ingestion of 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 man with bipolar disorder who switched to mania after consuming ayahuasca, a beverage containing DMT.

[0127] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0128] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the compound to be administered must be appropriately selected and preferably administered according to a specific dosing regimen.

[0129] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic drug of particular interest for therapeutic use. 5-MeO-DMT possesses unique pharmacological properties that are distinct from other psychedelic compounds.

[0130] 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 than other classic psychedelic drugs.

[0131] As further detailed in the Examples section below, the inhibitory constants (K) for psilocin dephosphate (the dephosphorylated form of psilocybin formed after ingestion of psilocybin), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin, DMT, and 5-MeO-DMT at the 5-HT2A receptor in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while dephosphopsilin and DMT exhibit intermediate affinity. i The values ​​for 5-MeO-DMT and 5-HTP-DMT were 37, 117, and 122 nM, respectively. Thus, dephosphopsilin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0132] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits enhanced affinity for the 5-HT1A receptor, acting as a potent agonist in this setting. The contribution of 5-HT2A binding is increased in the case of dephosphopsilin and DMT relative to 5-MeO-DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Therefore, 5-HT1A binding, relative to 5-HT2A binding, plays a much larger role in 5-MeO-DMT's overall effects than in the other two compounds.

[0133] 5-HT1A agonism has been reported to reduce impulsivity and aggression, while 5-HT2A agonism can lead to short-term increases in these same traits. Furthermore, the dopamine system has been implicated in the development of mania, with increased dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0134] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using the dosing regimens described herein without a significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I and bipolar II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

[0135] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate the use of a wide range of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0136] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of accompanying adverse events.

[0137] Furthermore, antidepressants have been reported to induce isolated hypomanic episodes 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.

[0138] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective, described as a "loss of self," typically culminating in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after inhalation, compared to hours with, for example, oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0139] In addition, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [3H]LSD as radioligand and serotonin to estimate nonspecific binding and determined K i The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation.

[0140] Another characteristic of 5-MeO-DMT is its short half-life.

[0141] 5-MeO-DMT is primarily inactivated through a deamination pathway mediated by monoamine oxidase A and O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0142] The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after administration.

[0143] Analysis of the pharmacokinetic properties of 5-MeO-DMT following inhalation revealed a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations had fallen to 10% or less of Cmax; after two hours, concentrations were 1% or less of Cmax; and after three hours, 5-MeO-DMT was no longer detectable in plasma. This applied to the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed after repeated administration over a timeframe of one to four hours. Up-titration as disclosed herein did not result in accumulation and, therefore, did not result in higher plasma concentrations, for example, at 10 minutes, two hours, or three hours after administration.

[0144] The properties of 5-MeO-DMT make the compound particularly suitable for treating sleep disorders, and particularly for treating patients suffering from psychiatric or neurological disorders.

[0145] The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

[0146] 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.

[0147] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0148] A deuterated form of 5-MeO-DMT is one that has a higher deuterium content than would be expected based on the natural abundance of the isotope.

[0149] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0150] 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.

[0151] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

[0152] Methods for the preparation of these compounds are known in the art.

[0153] Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0154] Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

[0155] 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 can be converted to 5-MeO-DMT through metabolism. Therefore, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be substituted.

[0156] In suitable prodrugs, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0157] An example of a suitable organic moiety is C(O)OR 1 、-C(O)R 2 、-CH(R 3 )OR 4 、-C(O)OCH(R 3 )OC(O)R 4 、-C(O)OCH(R 3 )OC(O)OR 4 、-CH(R 3 )C(O)R 4 、-CH(R 3 )OC(O)R 4 、-CH(R 3 )OC(O)OR 4 , where R 1 、R 2 、R 3 and R 4 Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0158] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 、R 3 and R 4 As defined above.

[0159] Prodrugs, especially those of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0160] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0161] Methods for preparing prodrugs as discussed herein are known in the art.

[0162] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hour or less, especially 0.5 hour or less.

[0163] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0164] Mode of administration

[0165] Therapeutically effective amounts of 5-MeO-DMT are administered by inhalation, nasal administration, buccal administration, or sublingual administration. Administration via these routes ensures rapid onset of action. The most preferred route of administration is by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0166] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal formulation, examples of which are known in the art. For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably the hydrobromide salt) or in the form of a formulation of a pharmaceutically acceptable salt (preferably the hydrobromide salt). Examples of suitable devices are known in the art.

[0167] Buccal or sublingual administration may also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, preferably the hydrobromide salt, either per se or in the form of a formulation, such as a tablet, film, spray, or cream, as is known in the art.

[0168] Administration is particularly performed by inhalation of an aerosol. This aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of 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, in particular about 2 mg / l to about 9 mg / l. The pharmaceutically acceptable gas is preferably air.

[0169] The aerosol particles preferably contain less than 1% by weight of impurities, in particular less than 0.5% by weight of impurities. In addition, they preferably contain less than 0.5% by weight of 5-MeO-DMT degradation products, in particular less than 0.2% by weight of 5-MeO-DMT degradation products, which are produced by chemical modifications of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0170] In a further preferred aspect, the aerosol consists essentially of: (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0171] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0172] The aerosol is preferably characterised by having a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular less than 2 μm and greater than 0.1 μm.

[0173] An aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT to generate aerosol particles. The thin layer can have a thickness of less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness 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.

[0174] The thin layer of 5-MeO-DMT disposed on the solid support can be exposed to thermal energy by passing air through the thin layer. Alternatively, the thin layer of 5-MeO-DMT disposed on the solid support can be exposed to thermal energy via the solid support.

[0175] The air passing through the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the thin layer may in particular have a temperature of about 210° C. and pass through the thin layer at a rate of about 12 l / min for about 15 seconds.

[0176] The aerosol particles may be contained in a volume equal to or less than about 3 liters, in particular in a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. Delivery to the patient is preferably via a single inhalation.

[0177] 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. These aerosols have an appropriate aerosol particle mass density such that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

[0178] Aerosols that can be used in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is difficult to predict which conditions are suitable for safe, efficient, and predictable aerosolization, particularly when the aerosol is to be used for systemic delivery of the compound to a patient via the lungs. Relevant variables in this context include a) the dosage of the compound, b) the morphological state (e.g., crystalline or thin layer form) of the compound that can be used for aerosolization, c) the amount of thermal energy to which the compound is exposed (defined by temperature and exposure duration), and d) the volume of air introduced to form the aerosol (defined by flow rate and airflow duration).

[0179] The compositions and methods described herein are used to safely, efficiently, and predictably deliver 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, to a patient systemically by inhalation. "Safe" means that the aerosol particles should contain only minimal amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized to a specified extent, preferably nearly completely or completely, i.e., the aerosol has the desired physical properties so that the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is delivered systemically through the lungs primarily via absorption in the alveoli and that the patient can inhale the aerosol in a single inhalation (i.e., within one deep breath), and "predictable" means that there is little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0180] A suitable aerosol can be achieved by a) providing a therapeutically effective amount of 5-MeO-DMT in the form of a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to an elevated, controlled temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

[0181] A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a thin layer of 5-MeO-DMT disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% by weight impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

[0182] An aerosol volume deliverable to a patient via a single inhalation, characterized by a mass median aerodynamic diameter of less than 3 microns, less than 1 weight percent impurities, and less than 0.5 weight percent 5-MeO-DMT drug degradation products, can be generated by defining: a) the dose of 5-MeO-DMT contained in the thin 5-MeO-DMT layer, b) the thickness of the 5-MeO-DMT layer, c) the thermal energy to which the thin 5-MeO-DMT layer is exposed (defined by the temperature and the duration of the exposure), and d) the total amount of air that passes through the thin 5-MeO-DMT layer (defined by the airflow rate and the duration of the airflow).

[0183] Preferably, the 5-MeO-DMT layer is exposed to thermal energy via air passing through the layer, in which case the air is heated. The heated air passing through the layer may have a temperature in the range of about 180° C. to about 260° C. The air passing through the layer may particularly have a temperature of about 210° C.

[0184] Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy via a solid support, in which case the air passing through the thin layer is not heated, but the solid support is heated. The heated solid support may have a temperature in the range of about 180°C to about 420°C.

[0185] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, at least 99%, preferably at least 99.5%.

[0186] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT disposed on the solid support is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 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. Preferred specific amounts include, for example, about 6 mg, about 12 mg, and about 18 mg.

[0187] 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, cylinders having a diameter of less than 1.0 mm, boxes having a thickness of less than 1.0 mm, and virtually any shape that is filled with small pores (e.g., less than 1.0 mm in size). Preferably, the solid support provides a large surface area to volume ratio (e.g., greater than 100 m / m) and a large surface area to mass ratio (e.g., greater than 1 cm 2 / gram).

[0188] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet with a thickness of 0.25 mm has a surface area to volume ratio of approximately 8,000 / m. Rolling the sheet into a hollow cylinder with a diameter of 1 cm produces a support that retains the high surface area to mass ratio of the original sheet, but has a lower surface area to volume ratio (about 400 / m).

[0189] A variety of different materials can be used to construct the solid support. Classes of such materials include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of material classes: 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 variations of material coatings can also be used.

[0190] When aluminum is used as a 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 (Aldrich, St. Louis, Mo.), and a crystalline silica having a defined surface area greater than 2 m 2 / g of aluminum oxide) and silicon wafers used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0191] Preferably, the thickness of the 5-MeO-DMT layer disposed on the solid support is less than about 10 μm, particularly less than about 7.5 μm. The layer may have a thickness in the range of about 0.1 μm to about 10 μm, particularly in the range of 0.3 μm to 7.5 μm.

[0192] Preferably, the total amount of air passing through the 5-MeO-DMT thin layer is limited to about 6 liters / minute to about 40 liters / minute, preferably about 8 liters / minute to about 16 liters / minute flow velocity, and select the persistent period of air-flow so that the cumulative volume of aerosol is no more than about 3 liters, preferably about 1 rises to 3 liters, such as 2 rises to 3 liters.For example, when air flow rate was about 6 liters / minute, the air flow persistent period should be less than about 30 seconds.A useful specific air flow rate and persistent period were about 12 liters / minute and about 15 seconds, thereby produced about 3 liters of aerosol volume.Another useful specific air flow rate and persistent period were 10 liters / minute and about 15 seconds, thereby produced about 2.5 liters of aerosol volume.Another useful specific air flow rate and persistent period were 8 liters / minute and about 15 seconds, thereby produced about 2 liters of aerosol volume.Another useful specific air flow rate and persistent period were 10 liters / minute and about 12 seconds, thereby produced about 2 liters of aerosol volume.

[0193] The aerosol formation rate is greater than 0.1 mg / second.

[0194] The aerosol has an aerosol particle mass density of 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, in particular about 2 mg / l to about 9 mg / l.

[0195] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, and most preferably less than 2 microns and greater than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% impurities by weight, preferably less than 0.5% impurities by weight.

[0196] The 5-MeO-DMT aerosol particles are characterized by less than 0.5 weight percent 5-MeO-DMT degradation products, preferably less than 0.2 weight percent 5-MeO-DMT degradation products.

[0197] A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by: a) exposing a 12 mg dose of 5-MeO-DMT configured as a thin layer less than 5 microns thick on a solid support to a temperature of 210° C. for 15 seconds by passing heated air through the thin layer; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% impurities and less than 0.5% by weight of 5-MeO-DMT degradation products, and 3) it can be delivered to a patient via a single inhalation.

[0198] Those skilled in the art who understand the aerosol characteristics defined in the present invention and aerosolization conditions can determine suitable gasification device or system, which results in required aerosol characteristics. The example of such suitable gasification device or system includes, for example, the Volcano Medic gasification system (Storz&Bickel, Germany) with a related dosing capsule with a drip pad; Disclosed in, for example, EP 0 933 093 B1 and EP 1 884 254 B1 and registered community design 003387299-0001) and Staccato device (Alexza Pharmaceuticals, Mountain View, USA; Disclosed in, for example, US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The aerosol generated can be collected in the balloon and inhaled from the balloon by the patient.

[0199] Dosage regimen

[0200] The present invention also provides dosage ranges, specific dosages, and dosing regimens (administration schedules).

[0201] The present invention is based in part on the inventors' conclusion that the peak psychedelic experience occurs during the acute phase following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, and that this drives the therapeutic benefit of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, in patients suffering from sleep disorders, particularly one or more of the aspects defined above, either causally or as a surrogate behavioral marker of an underlying unknown therapeutic mechanism.

[0202] Therefore, achieving peak experiences more quickly in a greater proportion of patients and with better reproducibility within individual patients will lead to a better therapeutic profile than with previously tested psychedelics and dosing regimens.

[0203] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in somatic side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with typical psychedelic experiences and allows for preparation for the more intense symptoms that occur at higher doses, which will positively impact the experience at higher doses. Furthermore, the prospect of being able to initiate treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0204] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the reproducibility of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be achievable with other psychedelics due to their delayed onset and prolonged duration of effects and the rapid development of tolerance (i.e., diminished or absent effects upon re-administration), which may persist for several days.

[0205] A patient suffering from a sleep disorder as defined herein is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0206] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other sleep disorder treatment.

[0207] The dosage of 5-MeO-DMT administered to a patient suffering from a sleep disorder as defined herein is in the range of about 1 mg to about 25 mg, or any amount within that range, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Specific amounts that are useful 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. Patients may also receive an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Please note that throughout this specification, when a range is listed (such as "about 1 mg to about 25 mg"), the inventors contemplate all discrete values ​​within that range, some of which are explicitly mentioned, but not all of which are - this is for the sake of brevity only.

[0208] In preferred embodiments, the improved method of treating a patient suffering from a sleep disorder as defined herein using a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response no later than about 2 hours after administration of the 5-MeO-DMT.

[0209] In preferred embodiments, improved methods of treating patients suffering from sleep disorders as defined herein with a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0210] In a preferred embodiment, the improved method of treating a patient suffering from a sleep disorder as defined herein with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0211] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0212] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0213] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block being no less than about 6 days.

[0214] In an embodiment, the dose of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for the individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Specific amounts that are useful 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.

[0215] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg at the first administration within each treatment block and is increased with each subsequent administration within each treatment block until it reaches 20 mg, or all administrations within the treatment block have been administered, whichever is earlier.

[0216] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg upon the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 20 mg, or all administrations within the treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further dose increases are inappropriate based on observed side effects.

[0217] For embodiments in which the dose of a subsequent administration is increased, the dose 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 dose of the previous administration. For example, if the first administration dose is 6 mg and the dose increase is 6 mg, the second administration dose is 12 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administration dose is 18 mg.

[0218] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased to a dose selected from about 8 mg to about 14 mg for the second administration, and to a dose selected from about 14 mg to about 20 mg for the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Specific useful amounts for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0219] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 2 mg to about 8 mg and is then increased with each subsequent administration within the first treatment block until the earlier of: reaching 20 mg, or all administrations within the treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further dose increases are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will serve as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block was 18 mg because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 18 mg.

[0220] In a most preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient during the first administration of the first treatment block is selected from the range of about 2 mg to about 8 mg, and then, unless the patient has experienced a peak psychedelic experience during the treatment block or the attending physician determines that further increases in dose are inappropriate based on observed side effects, the second administration of the first treatment block is increased to a dose selected from the range of about 8 mg to about 14 mg, and the third administration of the first treatment block is increased to a dose selected from the range of about 14 mg to about 20 mg, wherein the highest dose in the first treatment block is used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific useful amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0221] It will be understood that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosage regimens, and that the appropriate weight of salt to be administered can be calculated based on the stated weight of the free base, assuming equimolar amounts are used.

[0222] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0223] A patient can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0224] Patients experiencing a “peak psychedelic experience” can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Nowhereness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0225] According to the present invention, whether a patient has had a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score from 0 to 100 of the patient's responses to the following three questions: 1. How intense was the experience? 2. How much loss of control was there? 3. How significant (i.e., profound and important) was the experience?

[0226] Treatment of sleep disorders and psychiatric and neurological disorders

[0227] According to the present invention, idiopathic sleep disorders and sleep disorders in patients suffering from mental disorders or nervous system disorders can be treated. In patients suffering from sleep disorders associated with mental disorders or nervous system disorders, the treatment of sleep disorders according to the present invention leads to improvement of diseases associated with sleep disorders.

[0228] In many cases, resting-state networks involved in sleep disturbances are also implicated in these disorders.

[0229] 5-MeO-DMT disrupts established functional connectivity patterns in resting-state networks. This disruption leads to the resetting of pathological, dysfunctional brain connections as the networks rewire. New, healthy functional connections are established, and the effects are long-lasting.

[0230] The persistent nature of these effects may be explained by 5-MeO-DMT's neuroplasticity-promoting properties. 5-MeO-DMT specifically promotes structural and functional plasticity at synapses (the sites where neurons connect and communicate with each other). 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, thereby initiating the formation of new synaptic connections. These new connections can be strengthened, weakened, or even eliminated depending on activity.

[0231] The resulting formation of new synapses, in turn, influences the activity patterns of neurons. The inventors conclude that this reciprocal structural and functional modification contributes to the proper establishment of networks and the persistence of the effects following 5-MeO-DMT administration.

[0232] Biochemically, 5-MeO-DMT interacts with the 5-HT receptor.

[0233] 5-HT receptors, receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A variety of physiological and pathological functions are mediated by these receptors.

[0234] Seven types of 5-HT receptors are expressed in the brain, which can be further divided into several subtypes. Each type and subtype displays distinct spatial distributions.

[0235] 5-MeO-DMT interacts with several 5-HT receptors, which are involved in mediating its effects on resting-state networks and neural plasticity.

[0236] In addition to the 5-HTAl and 5-HT2A discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist for this receptor and exhibits high (nanomolar) binding affinity.

[0237] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis, and dendritic spine formation. It is implicated in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0238] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0239] The suprachiasmatic nucleus (SCN) is the central pacemaker of the circadian timing system. It coordinates circadian rhythms across various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disturbances. Resting-state functional connectivity analysis has revealed altered functional connectivity between the SCN and regions within the default mode network in patients with sleep disturbances.

[0240] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of these receptors in regulating the sleep / wake cycle. The inventors believe that this allows for the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0241] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0242] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal. This is supported by the clinical results demonstrated in the studies cited herein.

[0243] Treatment according to the invention will result in an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric or neurological disorder, also in an improvement in said disorder.

[0244] Clinical data from studies of patients with treatment-resistant depression (TRD) or postpartum depression (PPD) demonstrate that sleep disturbances can be successfully treated by administering 5-MeO-DMT.

[0245] In the TRD study described in more detail in the Examples section below, the MADRS item "Sleep reduction" reflecting insomnia was assessed, among others.

[0246] The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the participant's normal sleep pattern when healthy. A score of 0 indicates normal sleep. A score of 2 reflects mild difficulty falling asleep or slightly reduced, shallow, or fragmented sleep. A score of 4 indicates reduced or interrupted sleep of at least two hours. A score of 6 indicates sleep duration of less than two or three hours.

[0247] In the study group that received the individualized dosing regimen, all eight patients had a total score of 25 for the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score had decreased to 12, corresponding to an improvement of 13 points, or 52%. On day 7 after treatment, the score had decreased to 9, corresponding to an improvement of 16 points, or 64%.

[0248] In the 12 mg group, all four patients had a total score of 12 for the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0249] Therefore, the score of the scale item "sleep loss" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance, especially in patients suffering from mental disorders or neurological disorders.

[0250] Idiopathic sleep disorders

[0251] Treatment of a patient suffering from idiopathic sleep disorder with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the idiopathic sleep disorder.

[0252] Reduction or elimination of idiopathic sleep disturbances is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0253] Reduction or elimination of idiopathic sleep disturbances preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of idiopathic sleep disturbances preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0254] In an embodiment, reduction or elimination of idiopathic sleep disturbances is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0255] In the case of idiopathic sleep disorders, a clinical response may be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S score is reduced by at least 1 point. Preferably, the CGI-S score is reduced by at least 2 points and / or is reduced to 0 points. Particularly preferably, the CGI-S score is reduced by at least 3 points and / or is reduced to 0 points.

[0256] Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0257] Improvement in idiopathic sleep disturbances, as reflected by a decrease in CGI-S scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0258] The improvement of idiopathic sleep disturbance (as reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0259] In an embodiment, improvement in idiopathic sleep disturbances (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 until at least 14 days, more preferably until at least 28 days.

[0260] In the case of idiopathic sleep disturbances, improvement in sleep disturbances (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) is observed on day 1, e.g., about 24 hours later; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0261] Improvement in idiopathic sleep disturbance (as reflected at least by a score of "much improved" on the CGI-I score or the PGI-I score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0262] The improvement in sleep disturbances (at least as reflected by a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0263] In an embodiment, improvement in idiopathic sleep disturbances (as reflected at least by a score of "much improved" on the CGI-I score or the PGI-I score) is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0264] In the case of idiopathic sleep disorders, improvement may also be assessed by any other scale reflecting changes in sleep quality or quantity as described above, such as the Pittsburgh Sleep Quality Index (PSQI).

[0265] If the PSQI is used to assess treatment outcome, treatment success is indicated by (i) a decrease in the overall score, preferably (ii) a decrease in the score to 5 or less. The recall period to be applied begins no earlier than the point in time after the last administration when the acute psychedelic experience has subsided.

[0266] Improvement in idiopathic sleep disturbances (as reflected by a decrease in the PSQI total score, particularly a decrease in the total score to 5 or below) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0267] This improvement in idiopathic sleep disturbance (reflected by a decrease in the PSQI total score, in particular a decrease in the total score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0268] Improvement in idiopathic sleep disturbances is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the PSQI total score, particularly a decrease in the total score to 5 or less.

[0269] In an embodiment, improvement in idiopathic sleep disturbances is observed on day 7, as reflected by a decrease in the PSQI overall score, particularly a decrease in the overall score to 5 or below, and preferably persists until day 14, more preferably until day 28.

[0270] Sleep disturbances associated with psychiatric and neurological disorders

[0271] Although disrupted sleep may be considered a condition that should be treated independently of any other conditions, disorders, or symptoms an individual may have, several psychiatric and neurological disorders are associated with disrupted sleep. Notably, the relationship between sleep and psychiatric or neurological disorders is often bidirectional. Not only can psychiatric or neurological disorders negatively impact healthy sleep patterns, but disrupted sleep can also contribute to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0272] The treatment method according to the present invention can reduce or eliminate sleep disturbances and preferably also improve related psychiatric or neurological disorders.

[0273] Disorders characterized by depressive episodes

[0274] Several disorders are characterized by depressive episodes.

[0275] A depressive episode is a period of depressed mood and / or loss of interest in most activities.

[0276] For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms within the same 2-week period that represent a change from previous functioning; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

[0277] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0278] During a depressive episode, people often suffer from insomnia or excessive sleeping.

[0279] Sleep disturbance is included in the diagnostic criteria for a disorder characterized by a depressive episode. It may be assessed as part of the MADRS or HAM-D assessment.

[0280] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0281] The items are overt sadness; reported sadness; inner tension; decreased sleep; decreased appetite; difficulty concentrating; laziness; sensory loss; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6. The overall score ranges from 0 to 60.

[0282] The item "Sleep reduction" reflects sleep disturbances compared to the subject's normal pattern when healthy, specifically experiences a decrease in sleep duration or depth. If the patient's sleep pattern is normal, the score is 0. If the patient has mild difficulty falling asleep, or sleep duration is slightly reduced, shallow, or fragmented, the score is 2. If sleep duration is reduced or interrupted for at least two hours, the score is 4. In cases where sleep duration is less than two or three hours, the score is 6.

[0283] The Hamilton Rating Scale for Depression (HAM-D) can help clinicians assess the nature and severity of mood disturbances in their patient population. The scale consists of 21 items, but only the first 17 items (depressed mood; guilt; suicidality; initial insomnia; nocturnal insomnia; delayed insomnia; work and interest; retardation; agitation; mental anxiety; somatic anxiety; gastrointestinal somatic symptoms; general somatic symptoms; genital symptoms; hypochondriasis; weight loss; and insight) are used for scoring.

[0284] For most questions, the score ranges from 0 to 4, with 4 indicating more severe signs of depression. A few questions extend the range to only 2. A total score is calculated, which can then be compared to previous scores or compared to predefined cutoff scores.

[0285] Initial insomnia reflects insomnia early in the night. A score of 0 is assigned if the patient has no difficulty falling asleep, a score of 1 is assigned if the patient complains of occasional difficulty falling asleep (ie, more than 1 / 2 hour), and a score of 2 is assigned if the patient complains of difficulty staying asleep at night.

[0286] Insomnia during the night (i.e., in the middle of the night) was scored as 0 if there were no difficulties; 1 if the patient complained of restlessness during the night; and 2 if the patient woke up during the night (any awakening other than for urination was scored as 2).

[0287] Delayed insomnia reflects difficulty falling asleep in the early morning hours, with a score of 0 if there is no difficulty falling asleep, a score of 1 if the patient wakes up in the early morning hours but can fall back asleep, and a score of 2 if the patient is unable to fall asleep again after getting up.

[0288] In patients with disorders characterized by depressive episodes, altered functional connectivity within and / or between several brain regions associated with processing, regulation, emotional memory, cognitive processes related to rumination, impaired concentration, and physiological arousal is observed.

[0289] Treatment of patients suffering from a disorder characterized by a depressive episode (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, reduces or eliminates the sleep disturbances and results in an improvement in the disorder characterized by a depressive episode.

[0290] Reduction or elimination of sleep disturbances in patients suffering from a disorder characterized by a depressive episode is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0291] Reduction or elimination of sleep disturbances in a patient suffering from a disorder characterized by a depressive episode occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0292] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a disorder characterized by a depressive episode is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0293] Improvements in sleep disturbances in patients suffering from a disorder characterized by a depressive episode, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0294] Improvement in sleep disturbance in patients suffering from a disorder characterized by a depressive episode (as reflected in a decrease in CGI-S score) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbance in patients suffering from a disorder characterized by a depressive episode (as reflected in a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0295] In an embodiment, improvement in sleep disturbance in patients suffering from a disorder characterized by a depressive episode (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0296] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in the score for the MADRS item sleep loss on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0297] The reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from a disorder characterized by a depressive episode (as reflected by an improvement in the score on the MADRS item Sleep decreased) occurs no later than 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 decreased sleep) in patients suffering from a disorder characterized by a depressive episode (as reflected by an improvement in the score on the MADRS item Sleep decreased) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0298] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from a disorder characterized by a depressive episode (as reflected in an improvement in the score of the MADRS item sleep loss) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0299] Reduction or elimination of sleep disturbances, particularly decreased sleep, in patients suffering from a disorder characterized by a depressive episode is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0300] The reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from a disorder characterized by a depressive episode (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) occurs no later than 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 decreased sleep) in patients suffering from a disorder characterized by a depressive episode (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0301] In an embodiment, a reduction or elimination of sleep disturbances, particularly decreased sleep, in patients suffering from a disorder characterized by a depressive episode (as reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0302] As described above, sleep disturbances are closely related to disorders characterized by depressive episodes. Therefore, improvements in sleep disturbances will also lead to improvements in disorders characterized by depressive episodes. Furthermore, because sleep disturbances can also affect other aspects of disorders characterized by depressive episodes, the inventors have concluded that improvements in sleep disturbances, particularly reduction or elimination of sleep loss, will additionally contribute to overall improvements in disorders characterized by depressive episodes.

[0303] Improvement in impairment characterized by a depressive episode in patients also suffering from an associated sleep disturbance, as reflected in a decrease in CGI-S scores, is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0304] Improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the CGI-S score) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the CGI-S score) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0305] In an embodiment, improvement in the disorder characterized by a depressive episode in patients also suffering from an associated sleep disturbance (as reflected in a decrease in CGI-S score) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0306] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects how a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0307] Patients may have moderate or severe MDD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or higher. Patients may further be considered to have severe major depressive disorder, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or higher.

[0308] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder (TRD).

[0309] In patients with MDD, functional connectivity impairments and modulations within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network, were observed. Functional connectivity differed significantly from that observed in healthy controls.

[0310] As mentioned above, functional connectivity disturbances in the resting-state network are also associated with sleep disorders such as insomnia and hypersomnia.

[0311] An estimated three-quarters of all patients with MDD experience some form of sleep disturbance, such as insomnia or excessive sleepiness, sometimes both simultaneously. In the DSM-5 criteria, sleep disturbance is one of nine symptoms, at least five of which must be present for a period of time to qualify for a diagnosis of MDD.

[0312] Sleep disturbances in the setting of MDD are associated with a greater risk of suicide and a significant decrease in patients' quality of life.

[0313] Treatment of patients suffering from MDD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the MDD.

[0314] Reduction or elimination of sleep disturbances in patients suffering from MDD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0315] Reduction or elimination of sleep disturbances in patients suffering from MDD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0316] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from MDD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0317] Improvements in sleep disturbances in patients suffering from MDD, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0318] Improvement in sleep disturbances in patients suffering from MDD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from MDD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0319] In an embodiment, improvement in sleep disturbances in patients suffering from MDD (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 until at least 14 days, more preferably until at least 28 days.

[0320] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from MDD is reflected in at least an improvement in the score for the MADRS item sleep deprivation on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0321] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from MDD (as reflected at least by an improvement in the score of the MADRS item sleep loss) occurs no later than 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 loss) in patients suffering from MDD (as reflected at least by an improvement in the score of the MADRS item sleep loss) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0322] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from MDD is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof (reflected by an improvement in the score of the MADRS item sleep deprivation), and preferably persists until at least 14 days, more preferably until at least 28 days.

[0323] Reduction or elimination of sleep disturbances in patients suffering from MDD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease in the total score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0324] Reduction or elimination of sleep disturbances in patients suffering from MDD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from MDD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0325] In an embodiment, a reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from MDD (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0326] As mentioned above, sleep disturbances are closely related to MDD. Therefore, improving sleep disturbances will also lead to improvements in MDD. In addition, because sleep disturbances can also affect other aspects of MDD, the inventors have concluded that improving sleep disturbances, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of MDD.

[0327] Improvements in major depressive disorder in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] Improvement in major depressive disorder in patients who also suffer from an associated sleep disturbance (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in major depressive disorder in patients who also suffer from an associated sleep disturbance (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0329] In an embodiment, improvement in MDD in patients also suffering from an associated sleep disturbance (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 until at least 14 days, more preferably until at least 28 days.

[0330] Sleep disturbances are also associated with postpartum depression (PPD).

[0331] More than 50% of women may experience a brief period of low mood or tearfulness after childbirth. However, a subset of women may develop PPD, a debilitating mood disorder that develops during pregnancy or within 4 weeks after childbirth. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0332] Patients may have moderate or severe PPD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher. Patients may further be considered to have severe PPD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or higher.

[0333] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

[0334] Furthermore, 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.

[0335] Furthermore, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0336] Patients suffering from PPD may suffer from a treatment-resistant form of the disorder.

[0337] Depression during the postpartum period not only affects the mother's overall health, but also affects how she interacts with her child, thereby affecting the child's development.

[0338] Sleep disturbances are a common symptom during pregnancy and are highly correlated with the development of depressive symptoms. Women with poor sleep quality are 3.34 times more likely to suffer from depression than those with good sleep quality.

[0339] Sleep disturbances during pregnancy are themselves a predictor of PPD.

[0340] The study showed that changes in sleep quality, rather than changes in the hormonal environment, were associated with PPD recurrence and severity.

[0341] PPD can be assessed using the Edinburgh Postnatal Depression Scale (EPDS), which rates how the mother has felt over the past seven days. Insomnia due to unhappiness is one of 10 questions assessed on the questionnaire. The rating range is "0" (no, not at all) to "3" (yes, most of the time). The threshold level for sleep disturbance is a total score of 13, and sleep disturbance can be considered an essential part of the PPD diagnosis.

[0342] In patients with PPD, significant changes in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition are observed. PPD is associated with functional impairments in resting-state networks, such as the default mode network and the frontoparietal network, within and / or between them.

[0343] Treatment of patients suffering from PPD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of PPD.

[0344] Reduction or elimination of sleep disturbances in patients suffering from PPD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0345] Reduction or elimination of sleep disturbances in patients suffering from PPD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0346] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from PPD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0347] Improvements in sleep disturbances in patients suffering from PPD, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] Improvement in sleep disturbances in patients suffering from PPD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from PPD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0349] In an embodiment, improvement in sleep disturbances in patients suffering from PPD (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 until at least 14 days, more preferably until at least 28 days.

[0350] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from PPD is reflected in at least an improvement in the score for the MADRS item sleep deprivation on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0351] The reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from PPD (as reflected by an improvement in the score of the MADRS item decreased sleep) occurs no later than 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 decreased sleep) in patients suffering from PPD (as reflected by an improvement in the score of the MADRS item decreased sleep) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0352] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from PPD is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof (reflected by an improvement in the score of the MADRS item sleep deprivation) and preferably persists until at least 14 days, more preferably until at least 28 days.

[0353] Reduction or elimination of sleep disturbances in a patient suffering from PPD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0354] Reduction or elimination of sleep disturbances in patients suffering from PPD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from PPD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0355] In an embodiment, a reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from PPD (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0356] As mentioned above, sleep disturbances are closely related to PPD. Therefore, improving sleep disturbances will also lead to improvements in PPD. In addition, because sleep disturbances can also affect other aspects of PPD, the inventors have concluded that improving sleep disturbances, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of PPD.

[0357] Improvements in postpartum depression in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0358] Improvement in postpartum depression (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in postpartum depression (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] In an embodiment, improvement in PPD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0360] In an embodiment, improvement in PPD in patients also suffering from associated sleep disturbances, as reflected by improvement in the Edinburgh Postnatal Depression Scale (EPDS), is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0361] Furthermore, sleep disturbances can impair maternal functioning.

[0362] For example, the Barkin Index of Maternal Functioning (BIMF) can be used to assess maternal function. This index is designed to measure functioning within one year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is scored from 0 to 6, for a maximum total score of 120. The higher the score, the better the assessment of maternal functioning.

[0363] The BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, management, and adjustment.

[0364] A BIMF score of 95 or less is herein considered to represent mild impairment of maternal function, a score of 80 or less is herein considered to represent impaired maternal function, and a score of 65 or less is herein considered to represent severe impairment of maternal function.

[0365] The inventors have determined that increased scores on the MADRS item "Sleep Reduction" have a negative impact on two aspects of maternal functioning: maternal ability to interact with the infant and maternal self-care. Increased scores on the MADRS item "Sleep Reduction" impair self-care, psychological well-being, and management.

[0366] Increased scores on the MADRS item sleep reduction impaired psychological well-being, social support, and management. Conversely, improvements on the MADRS items led to improved maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and / or management.

[0367] The inventors concluded that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in sleep disturbances, particularly reduction or elimination of sleep deprivation.

[0368] The inventors also concluded that alleviating or eliminating sleep loss by treating PPD patients resulted in a decrease in MADRS total score and in an improvement in maternal functioning as reflected by an increase in BIMF score.

[0369] The BIMF total score improves by 10% or more, preferably by 20% or more.

[0370] Improvement in maternal function in patients suffering from PPD is reflected in at least an improvement in the BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0371] Improvement in maternal function in patients suffering from PPD (as reflected at least in an improvement in the BIMF total score) occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected at least in an improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] persistent depressive disorder

[0373] Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed if depression is present most of the time, most of the time, for at least two years. Any symptom-free period is less than two months.

[0374] To be considered depressed, two or more of the following symptoms must be present: 1. Hopelessness; 2. Lack of 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.

[0375] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0376] In patients with persistent depressive disorder, altered functional connectivity was observed within and / or between several brain regions involved in processing, regulation, emotional memory, cognitive processes related to rumination, impaired concentration, and physiological arousal. Functional connectivity impairment was observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

[0377] Treatment of patients suffering from persistent depressive disorder (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the persistent depressive disorder.

[0378] Reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0379] Reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0380] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from persistent depressive disorder is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least day 14, more preferably until at least day 28.

[0381] Improvements in sleep disturbances in patients suffering from persistent depressive disorder, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0382] Improvement in sleep disturbances in patients with persistent depressive disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients with persistent depressive disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0383] In an embodiment, improvement in sleep disturbances in patients suffering from persistent depressive disorder (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0384] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score for the MADRS item sleep loss on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0385] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from persistent depressive disorder (at least as reflected by an improvement in the score of the MADRS item sleep loss) occurs no later than 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 loss) in patients suffering from persistent depressive disorder (at least as reflected by an improvement in the score of the MADRS item sleep loss) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0386] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from persistent depressive disorder (as reflected in an improvement in the score of the MADRS item sleep loss) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0387] Reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease in the total score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0388] Reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0389] In an embodiment, a reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from persistent depressive disorder (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0390] As mentioned above, sleep disturbances are closely related to persistent depressive disorder. Therefore, improving sleep disturbances will also lead to improvement in persistent depressive disorder. In addition, because sleep disturbances can also affect other aspects of persistent depressive disorder, the inventors have concluded that improving sleep disturbances, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of persistent depressive disorder.

[0391] Improvements in persistent depressive disorder in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0392] Improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in persistent depressive disorder in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0393] In an embodiment, improvement in persistent depressive disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0394] Sleep disturbances are also a common symptom of seasonal affective disorder.

[0395] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms typically beginning in the fall and easing in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0396] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0397] People with seasonal affective disorder often experience extreme daytime sleepiness, sleep longer than usual at night, have difficulty waking from long sleep periods, or feel the need to take repeated naps throughout the day, even though naps may not relieve sleepiness. People with seasonal affective disorder also often experience nightmares.

[0398] Sleep duration related to the month and season is a core item in the assessment of seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire (SPAQ). Participants are asked to rate the seasonal changes they experience in sleep, social interaction, mood, weight, appetite, and energy, with three of the six questions related to sleep.

[0399] Resting-state activity involving sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0400] In patients with seasonal affective disorder, altered functional connectivity was observed within and / or between several brain regions associated with processing, regulation, emotional memory, cognitive processes related to rumination, impaired concentration, and physiological arousal. Functional connectivity impairments were observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

[0401] Treatment of patients suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of seasonal affective disorder.

[0402] Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0403] Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0404] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0405] Improvements in sleep disturbances in patients suffering from seasonal affective disorder, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0406] Improvement in sleep disturbances in patients with seasonal affective disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients with seasonal affective disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0407] In an embodiment, improvement in sleep disturbances in patients suffering from seasonal affective disorder (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 until at least 14 days, more preferably until at least 28 days.

[0408] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from seasonal affective disorder is reflected in at least an improvement in the score for the MADRS item sleep deprivation on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0409] The reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from seasonal affective disorder (as reflected by an improvement in the score of the MADRS item Sleep decreased) occurs no later than 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 decreased sleep) in patients suffering from seasonal affective disorder (as reflected by an improvement in the score of the MADRS item Sleep decreased) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from seasonal affective disorder (as reflected by an improvement in the score of the MADRS item sleep deprivation) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0411] Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0412] Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0413] In an embodiment, a reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from seasonal affective disorder (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0414] As mentioned above, sleep disturbances are closely related to seasonal affective disorder. Therefore, improving sleep disturbances will also lead to improving seasonal affective disorder. In addition, because sleep disturbances can also affect other aspects of seasonal affective disorder, the inventors have concluded that improving sleep disturbances, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of seasonal affective disorder.

[0415] Improvements in seasonal affective disorder in patients who also suffer from an associated sleep disturbance, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0416] Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disturbance (as reflected in a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disturbance (as reflected in a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0417] In an embodiment, improvement in seasonal affective disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S scores) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0418] Bipolar disorder (BD) is a mental health condition characterized by dramatic mood swings, including periods of low mood (major depressive episodes) and elevated mood (manic or hypomanic episodes). BD is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0419] Patients suffering from BD may suffer from treatment-resistant forms of the disorder.

[0420] If there is at least one manic episode (with or without a depressive episode), BD is classified as bipolar I. If there is at least one hypomanic episode (but not a full-blown manic episode) and one major depressive episode, BD is classified as bipolar II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

[0421] Patients with BD, whether diagnosed with bipolar II or bipolar I, are particularly susceptible to experiencing a current major depressive episode.

[0422] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score equal to or greater than 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0423] Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0424] Patients with BD (including bipolar I and bipolar II) are particularly prone to sleep disturbances, including changes in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities.

[0425] A decreased need for sleep is often a sign of a manic episode.

[0426] Disruption of the normal sleep-wake cycle has been implicated in the psychopathology of bipolar disorder, and circadian system dysregulation is considered a biomarker for bipolar disorder.

[0427] During a manic episode, 69%-99% of patients experience sleep disturbances.

[0428] Sleep disturbances can lead to earlier relapse and decreased quality of life (reduced healthy behaviors and increased suicide risk).

[0429] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. BDRS has been validated by trained assessors and can be used clinically. Based on clinical interviews, the BDRS project assesses the severity of depression and / or mixed symptoms that the patient has shown in the current and past few days. If the current symptoms are inconsistent with the symptoms of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the highest possible score is 60. The higher the score, the higher the severity.

[0430] Questions address depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; instability; increased drive to move; increased verbalizing; and agitation.

[0431] Each of these aspects is assessed and assigned a score of 0, 1, 2, or 3.

[0432] Sleep disturbances (sleep disorders) are assessed based on changes in the total amount of sleep over a 24-hour period and are not influenced by external factors. The sleep disturbances can manifest as insomnia (reduction in total sleep time) or hypersomnia (increase in total sleep time, including daytime sleep time).

[0433] The assessment of insomnia (reduction in total sleep time) included scores of 0 (no reduction in total sleep time); 1 (mild; reduction of up to 2 hours); 2 (moderate; reduction of 2-4 hours); and 3 (severe; reduction of more than 4 hours).

[0434] Alternative measures of excessive sleepiness (increase in total sleep time, including daytime sleep) include scores of 0 (no increase in total sleep time, including daytime sleep time); 1 (mild; increase of less than 2 hours, or normal amount but not restorative); 2 (moderate; increase of 2-4 hours); and 3 (severe; increase of more than 4 hours).

[0435] Patients with bipolar disorder exhibit characteristic abnormalities in the intrinsic organization and interconnectivity of resting-state networks. Resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity within and / or between specific regions of the default mode network, salience network, and central executive network compared to healthy controls. Altered functional connectivity within the default mode network has also been observed in patients with sleep disturbances.

[0436] Treatment of patients suffering from BD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of BD.

[0437] Reduction or elimination of sleep disturbances in patients suffering from BD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0438] Reduction or elimination of sleep disturbances in patients suffering from BD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from BD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0439] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from BD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0440] Improvements in sleep disturbances in patients suffering from BD, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0441] Improvement in sleep disturbances in patients suffering from BD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from BD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0442] In an embodiment, improvement in sleep disturbances in patients suffering from BD (reflected by a decrease in CGI-S score) is observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0443] Reduction or elimination of sleep disturbances in a patient suffering from BD can be reflected at least in an improvement in the score of the BDRS item Sleep Disturbance on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] The reduction or elimination of sleep disturbances in patients suffering from BD (as reflected by an improvement in the score of the BDRS item Sleep Disturbance) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from BD (as reflected by an improvement in the score of the BDRS item Sleep Disturbance) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0445] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from BD (as reflected in an improvement in the score of the BDRS item Sleep Disturbance) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0446] Reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from BD is reflected in at least an improvement in the score of the MADRS item sleep deprivation on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0447] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from BD (as reflected by an improvement in the score of the MADRS item sleep loss) occurs no later than 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 loss) in patients suffering from BD (as reflected by an improvement in the score of the MADRS item sleep loss) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from BD is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof (reflected by an improvement in the score of the MADRS item sleep deprivation) and preferably persists until at least 14 days, more preferably until at least 28 days.

[0449] Reduction or elimination of sleep disturbances in patients suffering from BD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] Reduction or elimination of sleep disturbances in patients suffering from BD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from BD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0451] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from BD (reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0452] Reduction or elimination of sleep disturbances (particularly increased total sleep time) in patients suffering from BD is reflected in at least an improvement in the score of the BDRS item "Excessive Sleepiness" on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] The reduction or elimination of sleep disturbances (particularly increased total sleep time) in patients suffering from BD (as reflected by an improvement in the score of the BDRS item "Excessive Sleepiness") occurs no later than 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 suffering from BD (as reflected by an improvement in the score of the BDRS item "Excessive Sleepiness") preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] In an embodiment, a reduction or elimination of sleep disturbances (particularly increased total sleep time) in patients suffering from BD (as reflected in an improvement in the score of the BDRS item hypersomnia) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0455] As mentioned above, sleep disturbances are closely related to BD. Therefore, improving sleep disturbances will also lead to improvements in BD. In addition, because sleep disturbances also affect other aspects of BD, the inventors concluded that improving sleep disturbances will additionally contribute to the overall improvement of BD.

[0456] Improvements in BD in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] Improvement in BD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0458] In an embodiment, improvement in BD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0459] anxiety disorders

[0460] Anxiety disorders are mental health conditions. Symptoms include nervousness, feelings of panic and fear, as well as sweating and a racing heartbeat. Anxiety involves a complex system of cognitive, emotional, physiological, and behavioral responses related to preparing for anticipated events or situations that are perceived as threatening.

[0461] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0462] People with anxiety disorders often experience sleep disturbances, particularly insomnia. Excessive worry and fear can make it difficult to fall asleep and stay asleep throughout the night.

[0463] Insomnia can exacerbate anxiety, leading to a vicious cycle involving insomnia and anxiety.

[0464] The severity of anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), which consists of 14 items, each defined by a series of symptoms, and measures mental anxiety (agitation and psychological distress) and somatic anxiety (physical discomfort related to anxiety). Item 4 is "insomnia," defined as "difficulty falling asleep, interrupted sleep, unsatisfactory sleep and feeling tired when waking up, dreaming, nightmares, and night terrors." Each item is scored on a scale of 0 (absent) to 4 (severe), with a total score range of 0-56.

[0465] Sleep disturbances can also be assessed using, for example, the Pittsburgh Sleep Quality Index (PSQI) overall score.

[0466] Anxiety disorders are associated with altered functional connectivity in resting-state networks. Anxiety disorders manifest as abnormalities in the default mode network (DMN), which influences self-perception; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. Relative to the DMN, resting-state balance within and / or between each of these networks (e.g., the SMN and SN) may be abnormal in different anxiety disorders.

[0467] Altered functional connectivity within the affected networks has also been associated with sleep disturbances, and anxiety disorders have been linked to sleep disturbances.

[0468] Treatment of patients suffering from anxiety disorders (including treatment-resistant forms of such disorders) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the anxiety disorder.

[0469] Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0470] Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0471] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0472] Improvements in sleep disturbances in patients suffering from anxiety disorders, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0473] Improvement in sleep disturbances in patients suffering from anxiety disorders (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from anxiety disorders (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] In an embodiment, improvement in sleep disturbances in patients suffering from an anxiety disorder (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 until at least 14 days, more preferably until at least 28 days.

[0475] Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0476] Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from anxiety disorders (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0477] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from an anxiety disorder (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0478] As mentioned above, patients with anxiety disorders experience sleep disturbances. Therefore, improving sleep disturbances will also lead to improvements in anxiety disorders. In addition, because sleep disturbances can also affect other aspects of anxiety disorders, the inventors have concluded that improving sleep disturbances will additionally contribute to the overall improvement of anxiety disorders.

[0479] Improvements in anxiety disorders in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0480] Improvement in anxiety disorders (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in anxiety disorders (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0481] In an embodiment, improvement in anxiety disorders (reflected by a decrease in CGI-S scores) in patients also suffering from an associated sleep disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0482] Separation anxiety disorder is characterized by excessive anxiety about leaving home and / or being separated from people to whom the patient has strong emotional attachments.

[0483] Separation situations can cause people significant distress, and they may have difficulty attending school or work because of the separation. People with separation anxiety disorder may also experience excessive anxiety about unwelcome events that happen to important people in their lives, such as family members.

[0484] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0485] Separation anxiety disorder is associated with sleep disturbances. Disrupted sleep is even part of the diagnostic criteria for separation anxiety disorder. Sleep disturbances in people with separation anxiety disorder include nightmares, difficulty falling asleep or staying asleep, early awakenings, and parasomnias.

[0486] The severity of separation anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbance is an integral part of the scale. By applying the scale before and after treatment, the scale can also be further used as an outcome measure for treatment according to the present invention.

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

[0488] Anxiety disorders are associated with altered functional connectivity in resting-state networks. Anxiety disorders manifest as abnormalities in the default mode network (DMN), which influences self-perception; the salience network (SN), which controls emotion / anxiety; and the somatomotor network (SMN), which is responsible for body awareness. Relative to the DMN, resting-state balance within and / or between each of these networks (e.g., the SMN and SN) may be abnormal in different anxiety disorders.

[0489] Altered functional connectivity within the affected network has also been associated with sleep disturbances, and separation anxiety disorder has been linked to sleep disturbances.

[0490] Treatment of patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement in the separation anxiety disorder.

[0491] Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0492] Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0493] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0494] Improvements in sleep disturbances in patients suffering from separation anxiety disorder, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0495] Improvement in sleep disturbances in patients suffering from separation anxiety disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from separation anxiety disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0496] In an embodiment, improvement in sleep disturbances in patients suffering from separation anxiety disorder (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 until at least 14 days, more preferably until at least 28 days.

[0497] Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0499] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder (reflected by an improvement in PSQI score, particularly a decrease in score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0500] As mentioned above, sleep disturbance is a major symptom of discomfort in patients with separation anxiety disorder. Therefore, improvement of sleep disturbance will also lead to improvement of separation anxiety disorder. In addition, since sleep disturbance can also affect other aspects of separation anxiety disorder, the inventors have concluded that improvement of sleep disturbance, in particular reduction or elimination of sleep loss, will additionally contribute to the overall improvement of separation anxiety disorder.

[0501] Improvements in separation anxiety disorder in patients who also suffer from an associated sleep disturbance, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] Improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in separation anxiety disorder in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0503] In an embodiment, improvement in separation anxiety disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0504] Agoraphobia is the fear of situations or places that could cause panic, feelings of being trapped, helpless, or embarrassed.

[0505] People with agoraphobia may have difficulty leaving the house. The thought of leaving the house may cause considerable anxiety, even leading to avoidance. Fears of crowds, travel, elevators, movie theaters, shopping malls, etc. may cause significant challenges.

[0506] People with agoraphobia may also experience recurring panic attacks.

[0507] Patients suffering from agoraphobia may suffer from a treatment-resistant form of the disorder.

[0508] Agoraphobia is associated with sleep disorders such as insomnia.

[0509] The severity of agoraphobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbances is an integral part of the scale. The scale can further be used as an outcome measure for treatment according to the present invention by applying the scale before and after treatment.

[0510] Sleep disturbances in agoraphobia can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0511] Functional magnetic resonance imaging of individuals with agoraphobia reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0512] Treatment of patients suffering from agoraphobia (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement in the agoraphobia.

[0513] Reduction or elimination of sleep disturbances in patients suffering from agoraphobia is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0514] Reduction or elimination of sleep disturbances in patients suffering from agoraphobia occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from agoraphobia preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0515] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from agoraphobia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0516] Improvements in sleep disturbances in patients suffering from agoraphobia, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0517] Improvement in sleep disturbances in patients suffering from agoraphobia (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from agoraphobia (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] In an embodiment, improvement in sleep disturbances in patients suffering from agoraphobia (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 until at least 14 days, more preferably until at least 28 days.

[0519] Reduction or elimination of sleep disturbances in patients suffering from agoraphobia is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0520] Reduction or elimination of sleep disturbances in patients suffering from agoraphobia (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from agoraphobia (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0521] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from agoraphobia (as reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0522] As mentioned above, sleep disturbance is a major symptom of agoraphobia. Therefore, improving sleep disturbance will also lead to improvement of agoraphobia. In addition, since sleep disturbance can also affect other aspects of agoraphobia, the inventors have concluded that improving sleep disturbance, especially reducing or eliminating sleep loss, will additionally contribute to the overall improvement of agoraphobia.

[0523] Improvement in agoraphobia in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S scores, is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0524] Improvement in agoraphobia in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in agoraphobia in patients who also suffer from an associated sleep disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] In an embodiment, improvement in agoraphobia in patients also suffering from an associated sleep disorder (as reflected in 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 until at least 14 days, more preferably until at least 28 days.

[0526] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and uncontrollable worry about a variety of situations and problems. People with GAD may anticipate disasters and worry excessively about money, health, family, work, or other issues.

[0527] Generalized Anxiety Disorder (GAD) is diagnosed when an individual experiences persistent worry about everyday challenges that is disproportionate to the perceived threat. People with GAD typically experience excessive fear that lasts for months to years.

[0528] GAD can interfere with social, occupational, or other important areas of functioning.

[0529] Patients suffering from GAD may suffer from a treatment-resistant form of the disorder.

[0530] A key feature of GAD is sleep disturbance, specifically difficulty falling asleep or staying asleep, or restless and unsatisfactory sleep. Sleep disturbance is associated with significant disability in GAD. In the DSM-5 criteria, sleep disturbance is one of six symptoms, at least three of which must be present for a period of time to qualify for a diagnosis of GAD.

[0531] The severity of generalized anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbances is an integral part of the scale. The scale can also be further used as an outcome measure for treatment according to the present invention by applying the scale before and after treatment.

[0532] Sleep disturbances in GAD can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0533] Patients with GAD also exhibit altered functional connectivity, particularly within the default mode network. Altered functional connectivity within the affected network has also been associated with sleep disturbances.

[0534] Treatment of patients suffering from GAD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of GAD.

[0535] Reduction or elimination of sleep disturbances in patients suffering from GAD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0536] Reduction or elimination of sleep disturbances in patients suffering from GAD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from GAD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from GAD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0538] Improvements in sleep disturbances in patients suffering from GAD, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] Improvement in sleep disturbances in patients suffering from GAD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from GAD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0540] In an embodiment, improvement in sleep disturbances in patients suffering from GAD (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 until at least 14 days, more preferably until at least 28 days.

[0541] Reduction or elimination of sleep disturbances in patients suffering from GAD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0542] Reduction or elimination of sleep disturbances in patients suffering from GAD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from GAD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0543] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from GAD (reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0544] As mentioned above, sleep disturbance is one of the most common major symptoms of patients with GAD. Therefore, improvement of sleep disturbance will also lead to improvement of GAD. In addition, since sleep disturbance can also affect other aspects of GAD, the inventors have concluded that improvement of sleep disturbance, particularly reduction or elimination of sleep loss, will additionally contribute to the overall improvement of GAD.

[0545] Improvements in GAD in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] Improvement in GAD (as reflected by a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in GAD (as reflected by a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] In an embodiment, improvement in GAD (as reflected in a decrease in CGI-S score) in patients also suffering from an associated sleep disturbance is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0548] Social anxiety disorder (SAD) is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations and can cause impairment in school, work, or interpersonal relationships.

[0549] Patients suffering from SAD may suffer from a treatment-resistant form of the disorder.

[0550] Sleep disturbances are very common in patients with social anxiety disorder due to the bidirectional relationship between sleep disturbances (primarily insomnia) and anxiety.

[0551] The severity of social anxiety disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbances is an integral part of the scale. The scale can further be used as an outcome measure for treatment according to the present invention by applying the scale before and after treatment.

[0552] Sleep disturbances in social anxiety disorder can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0553] In patients suffering from SAD, insomnia is reflected in 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.

[0554] Treatment of patients suffering from SAD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of SAD.

[0555] Reduction or elimination of sleep disturbances in patients suffering from SAD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0556] Reduction or elimination of sleep disturbances in patients suffering from SAD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from SAD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from SAD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0558] Improvements in sleep disturbances in patients suffering from SAD, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] Improvement in sleep disturbances in patients suffering from SAD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from SAD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] In an embodiment, improvement in sleep disturbances in patients suffering from SAD (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 until at least 14 days, more preferably until at least 28 days.

[0561] Reduction or elimination of sleep disturbances in patients suffering from SAD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] Reduction or elimination of sleep disturbances in patients suffering from SAD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from SAD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0563] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from SAD (reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0564] As mentioned above, sleep disturbance is a particularly important symptom for patients suffering from SAD. Therefore, improvement of sleep disturbance will also lead to improvement of SAD. In addition, since sleep disturbance can also affect other aspects of SAD, the inventors have concluded that improvement of sleep disturbance, in particular reduction or elimination of sleep loss, will additionally contribute to the overall improvement of SAD.

[0565] Improvements in SAD in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] Improvement in SAD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0567] In an embodiment, improvement in SAD (reflected by a decrease in CGI-S score) in patients also suffering from an associated sleep disturbance is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0568] People with panic disorder experience spontaneous panic attacks, which are sudden, intense fear or discomfort that peaks within a few minutes.

[0569] Panic attacks are characterized by multiple somatic symptoms of anxiety, including sweating, shaking, trembling, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0570] Additionally, the disorder can often be characterized by anxiety about future panic attacks. Sufferers may become extremely concerned about the possibility of another attack.

[0571] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0572] Sleep disturbances, particularly insomnia and hypersomnia, are very common in patients with panic disorder.

[0573] People with panic disorder may also experience nocturnal panic attacks, which are different from night terrors. These attacks can occur without a trigger and often make it difficult to get back to sleep.

[0574] The severity of panic disorder can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbances is an integral part. The scale can further be used as an outcome measure for treatment according to the present invention by applying it before and after treatment.

[0575] Sleep disturbances in panic disorder can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0576] 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, particularly the default mode network, is also a feature of insomnia and hypersomnia.

[0577] Treatment of patients suffering from panic disorder (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the panic disorder.

[0578] Reduction or elimination of sleep disturbances in patients suffering from panic disorder is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0579] The reduction or elimination of sleep disturbances in a patient suffering from panic disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from panic disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0580] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from panic disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0581] Improvements in sleep disturbances in patients suffering from panic disorder, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0582] Improvement in sleep disturbances in patients suffering from panic disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from panic disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] In an embodiment, improvement in sleep disturbances in patients suffering from panic disorder (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 until at least 14 days, more preferably until at least 28 days.

[0584] Reduction or elimination of sleep disturbances in patients suffering from panic disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease in the total score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0585] Reduction or elimination of sleep disturbances in patients suffering from panic disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from panic disorder (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0586] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from panic disorder (reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0587] As mentioned above, sleep disturbances are very common in patients with panic disorder. Therefore, improvement of sleep disturbances will also lead to improvement of panic disorder. In addition, because sleep disturbances can also affect other aspects of panic disorder, the inventors have concluded that improvement of sleep disturbances, particularly reduction or elimination of insomnia and / or excessive sleepiness, will additionally contribute to the overall improvement of panic disorder.

[0588] Improvements in panic disorder in patients who also suffer from an associated sleep disorder, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0589] Improvement in panic disorder in patients who also suffer from an associated sleep disorder (as reflected in a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in panic disorder in patients who also suffer from an associated sleep disorder (as reflected in a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] In an embodiment, improvement in panic disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0591] A phobia is an anxiety disorder characterized by a persistent, excessive fear of an object or situation. People with a phobia experience extreme anxiety when anticipating or coming into contact with the phobic stimulus. Examples include phobias of animals (spiders, snakes, dogs), natural environments (tornadoes, heights, water, fire), blood injections (needles, medical procedures), situations (flying, enclosed spaces), and others (those that don't fit into the aforementioned categories).

[0592] Phobias typically cause a rapid onset of fear that often persists for more than six months. Patients go to great lengths to avoid the phobic stimulus. Fear and avoidance can cause significant distress and / or impairment in occupational, academic, or social functioning.

[0593] Patients suffering from phobias may suffer from a treatment-resistant form of the disorder.

[0594] There is evidence that patients with phobias are more likely to experience sleep disturbances.

[0595] The severity of the phobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbances is an integral part. The scale can further be used as an outcome measure for treatment according to the present invention by applying it before and after treatment.

[0596] Sleep disturbances in phobias can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0597] Phobias are also reflected in altered functional connectivity in resting-state networks, such as those involving the amygdala and insula, and the salience network, which also plays a role in insomnia.

[0598] Treatment of patients suffering from phobias (including treatment-resistant forms of the disorders) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the phobias.

[0599] Reduction or elimination of sleep disturbances in patients suffering from phobias is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] The reduction or elimination of sleep disturbances in a patient suffering from a phobia occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in a patient suffering from a phobia preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a phobia is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0602] Improvements in sleep disturbances in patients suffering from phobias, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] Improvement in sleep disturbances in patients suffering from phobias (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from phobias (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] In an embodiment, improvement in sleep disturbances in patients suffering from phobias (reflected by a decrease in CGI-S scores) is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0605] Reduction or elimination of sleep disturbances in a patient suffering from a phobia is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0606] The reduction or elimination of sleep disturbances in patients suffering from phobias (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from phobias (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0607] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from a phobia (as reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0608] As mentioned above, patients with phobias are more likely to experience sleep disturbances. Therefore, improving sleep disturbances will also lead to improvements in phobias. In addition, because sleep disturbances can also affect other aspects of phobias, the inventors have concluded that improving sleep disturbances, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of phobias.

[0609] Improvements in phobias in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] Improvement in phobias (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in phobias (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0611] In an embodiment, improvement in phobia (as reflected in a decrease in CGI-S score) in patients also suffering from an associated sleep disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0612] Substance-induced anxiety disorder is an anxiety disorder in which anxiety or panic attacks occur after alcohol use, drug abuse, or medication use, or exposure to toxins. Substance-induced anxiety disorders cause significant panic or anxiety symptoms and may occur during periods of intoxication or withdrawal from substance use.

[0613] The disorder causes significant distress and / or impairment in social, occupational, or other important areas of functioning.

[0614] During or shortly after taking a substance or medication, individuals with substance / medication-induced anxiety disorder may feel nervous and worried, experience symptoms of negative thinking, may have difficulty concentrating or remembering things, may fear losing control or becoming delirious or dying, may lose weight due to gastrointestinal problems, may experience chills, hot flashes, sweating, shivering, numbness or a racing heartbeat, difficulty breathing, difficulty swallowing, or chest pain.

[0615] Patients suffering from substance / medication-induced anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0616] Substance-induced anxiety disorders are also associated with sleep disturbances. Patients may have trouble falling asleep or may wake frequently during the night.

[0617] The severity of substance / medication-induced anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), of which the assessment of sleep disturbances is an integral part. The scale can also be further used as an outcome measure for treatment according to the present invention by applying it before and after treatment.

[0618] Sleep disturbances in substance / medication-induced anxiety disorders can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0619] Functional magnetic resonance imaging of individuals with substance- / medication-induced anxiety disorders reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0620] Treatment of patients suffering from substance / medication induced anxiety disorders (including treatment-resistant forms of such disorders) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the substance / medication induced anxiety disorder.

[0621] Reduction or elimination of sleep disturbances in patients suffering from substance / medication induced anxiety disorders is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorders occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorders preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0623] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a substance / medication induced anxiety disorder is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0624] Improvements in sleep disturbances in patients suffering from substance / medication-induced anxiety disorders, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0625] Improvement in sleep disturbances in patients with substance / medication-induced anxiety disorders (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients with substance / medication-induced anxiety disorders (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0626] In an embodiment, improvement in sleep disturbances in patients suffering from substance / medication induced anxiety disorders (reflected by a decrease in CGI-S scores) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0627] Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorders is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease in the total score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorders (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from substance / medication-induced anxiety disorders (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from substance / medication induced anxiety disorders (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0630] As mentioned above, sleep disturbance is a major symptom of discomfort in patients with substance / drug-induced anxiety disorders. Therefore, improving sleep disturbance will also lead to improvement in substance / drug-induced anxiety disorders. In addition, because sleep disturbance can also affect other aspects of substance / drug-induced anxiety disorders, the inventors have concluded that improving sleep disturbance, particularly reducing or eliminating sleep loss, will additionally contribute to the overall improvement of substance / drug-induced anxiety disorders.

[0631] Improvements in substance / medication-induced anxiety disorders in patients who also suffer from associated sleep disturbances, as reflected in reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28.

[0632] Improvement in substance / medication-induced anxiety disorder (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in substance / medication-induced anxiety disorder (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] In an embodiment, improvement in substance / medication-induced anxiety disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0634] Somatic symptom disorder

[0635] Somatic symptom disorder is a mental disorder diagnosed when a person becomes so preoccupied with physical symptoms, such as pain, weakness, or shortness of breath, that it causes significant distress and / or problems functioning and / or disrupts their daily life. Feelings and behaviors associated with the disorder are excessive or disproportionate.

[0636] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorder, the impairment is significant, and when persistent, the disorder may lead to disability.

[0637] Patients with somatic symptom disorder may report disrupted sleep (ie, insomnia, dissatisfaction with the quality, timing, and quantity of sleep) that causes daytime distress and impairment.

[0638] Sleep disturbances have the potential to create a veritable vicious cycle between physical symptoms and sleep disturbance.

[0639] For example, insomnia is associated with the presence of somatic symptoms, and the severity of insomnia is associated with the severity of somatic symptoms. However, this effect is not limited to insomnia, as changes in the sleep-wake cycle itself have been associated with the occurrence of somatic symptoms.

[0640] Somatic symptom disorder can be assessed using the DSM-52 Somatic Symptom Measure-Adults. This measure includes 15 somatic symptoms. Respondents are asked to rate the severity of their individual somatic symptoms during the past 7 days. Sleep disturbances are analyzed by scoring "feeling tired or low on energy" and "trouble sleeping." Scores range from "0" ("not at all bothered"), "1" ("a little bothered") to "2" ("very bothered"). The total score can range from 0 to 30, with higher scores indicating more severe somatic symptoms. Cut-off values ​​of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0641] Additionally, the Pittsburgh Sleep Quality Index can be used to assess sleep disturbances in individuals with somatic symptom disorder.

[0642] Functional connectivity analysis revealed alterations within and / or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Alterations were found within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor networks. Somatic symptom disorder may be associated with alterations in the sensory discrimination processing of somatic symptoms, which is influenced by affective processing.

[0643] Treatment of patients suffering from somatic symptom disorder and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the somatic symptom disorder.

[0644] Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0645] Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] In embodiments, reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0647] Improvements in sleep disturbances in patients suffering from somatic symptom disorder, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0648] Improvement in sleep disturbances in patients suffering from somatic symptom disorder (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from somatic symptom disorder (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0649] In an embodiment, improvement in sleep disturbances in patients suffering from somatic symptom disorder (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 until at least 14 days, more preferably until at least 28 days.

[0650] Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) total score, particularly a decrease in the total score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0651] Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder (as reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0652] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0653] As mentioned above, sleep disturbances are common in patients with somatic symptom disorder. Therefore, improvement in sleep disturbances will also lead to improvement in somatic symptom disorder. In addition, because sleep disturbances can also affect other aspects of somatic symptom disorder, the inventors have concluded that improvement in sleep disturbances, particularly reduction or elimination of sleep loss, will additionally contribute to overall improvement in somatic symptom disorder.

[0654] Improvements in somatic symptom disorder in patients who also suffer from an associated sleep disorder, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0655] Improvement in somatic symptom disorder (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in somatic symptom disorder (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0656] In an embodiment, improvement in somatic symptom disorder (reflected by a decrease in CGI-S score) in patients also suffering from an associated sleep disorder is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0657] Obsessive-compulsive disorder and related disorders

[0658] Obsessive-compulsive disorder (OCD) is a mental illness that causes repetitive unwanted thoughts or feelings (obsessions) or the urge to do something over and over again (compulsions). People may experience both obsessions and compulsions.

[0659] Patients suffering from OCD may suffer from a treatment-resistant form of the disorder.

[0660] Sleep disturbances are a common feature of patients with OCD. The presence of sleep disturbances is correlated with the severity of OCD.

[0661] Sleep disturbances are associated with treatment resistance in OCD, and addressing symptoms will improve treatment outcomes.

[0662] 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 the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

[0663] Treatment of patients suffering from OCD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of OCD.

[0664] Reduction or elimination of sleep disturbances in patients suffering from OCD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0665] Reduction or elimination of sleep disturbances in patients suffering from OCD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from OCD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0666] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from OCD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0667] Improvements in sleep disturbances in patients suffering from OCD, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0668] Improvement in sleep disturbances in patients suffering from OCD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from OCD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] In an embodiment, improvement in sleep disturbances in patients suffering from OCD (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 until at least 14 days, more preferably until at least 28 days.

[0670] Reduction or elimination of sleep disturbances in patients suffering from OCD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0671] Reduction or elimination of sleep disturbances in patients suffering from OCD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from OCD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0672] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from OCD (as reflected by an improvement in the PSQI score, in particular a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0673] As mentioned above, sleep disturbances are common in patients with OCD. Therefore, improvement in sleep disturbances will also lead to improvement in OCD. In addition, because sleep disturbances can also affect other aspects of OCD, the inventors concluded that improvement in sleep disturbances, particularly reduction or elimination of sleep loss, will additionally contribute to overall improvement in OCD.

[0674] Improvements in OCD in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] Improvement in OCD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in OCD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0676] In an embodiment, improvement in OCD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0677] Individuals with body dysmorphic disorder (BDD) experience false perceptions of imperfections in their appearance that disrupt their ability to live daily lives and are accompanied by disturbing thoughts, ritualistic behaviors, and emotional distress.

[0678] Patients suffering from BDD may suffer from a treatment-resistant form of the disorder.

[0679] Sleep disturbances, particularly insomnia, are common features of patients with BDD and are associated with more severe psychopathology. Patients with BDD and sleep disturbances self-report higher BDD symptom severity, more depressive symptoms, and greater impairment in daily functioning.

[0680] Functional magnetic resonance imaging (fMRI) of patients with BDD has revealed alterations within and / or between certain brain regions within the default mode network, the dorsal attention network, and the salience network. Altered functional connectivity within the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

[0681] Treatment of patients suffering from BDD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of BDD.

[0682] Reduction or elimination of sleep disturbances in patients suffering from BDD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0683] Reduction or elimination of sleep disturbances in patients suffering from BDD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from BDD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0684] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from BDD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0685] Improvements in sleep disturbances in patients suffering from BDD, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0686] Improvement in sleep disturbances in patients suffering from BDD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from BDD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0687] In an embodiment, improvement in sleep disturbances in patients suffering from BDD (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 until at least 14 days, more preferably until at least 28 days.

[0688] Reduction or elimination of sleep disturbances in a patient suffering from BDD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] Reduction or elimination of sleep disturbances in patients suffering from BDD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from BDD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0690] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from BDD (as reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0691] As mentioned above, sleep disturbances are common in patients with BDD. Therefore, improvement in sleep disturbances will also lead to improvement in BDD. In addition, because sleep disturbances can also affect other aspects of BDD, the inventors concluded that improvement in sleep disturbances, particularly reduction or elimination of sleep loss, will additionally contribute to overall improvement in BDD.

[0692] Improvements in BDD in patients who also suffer from associated sleep disturbances, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0693] Improvement in BDD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BDD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] In an embodiment, improvement in BDD in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0695] Post-traumatic stress disorder (PTSD)

[0696] Post-traumatic stress disorder (PTSD) is a mental health condition that can develop after a person experiences or witnesses a terrifying event. Symptoms can include flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.

[0697] Patients suffering from PTSD may suffer from a treatment-resistant form of the disorder.

[0698] Sleep disturbances are associated with PTSD, with an estimated 70%-90% of patients reporting at least one type of sleep disturbance (insomnia, difficulty falling or staying asleep, parasomnias such as nightmares).

[0699] Sleep disturbance in the form of difficulty falling asleep, staying asleep, or restless sleep is one of six features of altered arousal, at least two of which are required for a diagnosis of PTSD according to DSM 5 criteria.

[0700] Sleep disturbances in PTSD can be assessed using self-administered questionnaires, such as the PTSD Symptom Inventory or the Trauma Screening Questionnaire (TSQ).

[0701] The self-report version of the PTSD Symptom Scale is a 17-item self-report questionnaire that assesses symptoms of post-traumatic stress disorder. Sleep disturbances are assessed as the presence of disturbing dreams or nightmares or difficulty falling or staying asleep. Respondents are asked to indicate how often they experienced certain sleep difficulties over the past two weeks or other appropriate recall window using a Likert-type scale ranging from 0 (not at all or only once) to 3 (almost always or five or more times per week). A score of 13 or higher indicates the likelihood of PTSD.

[0702] The trauma screening questionnaire includes 10 items, two of which analyze sleep (bad dreams, or difficulty falling asleep, or difficulty staying asleep), requiring a yes or no answer. Six or more positive answers indicate a risk for PTSD.

[0703] Resting-state functional magnetic resonance imaging analyses of patients with PTSD revealed alterations within and / or between regions within the default mode network and the salience network.

[0704] Treatment of patients suffering from PTSD (including treatment-resistant forms of the disorder) and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement in PTSD.

[0705] Reduction or elimination of sleep disturbances in patients suffering from PTSD is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0706] The reduction or elimination of sleep disturbances in patients suffering from PTSD occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of sleep disturbances in patients suffering from PTSD preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0707] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from PTSD is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0708] Improvements in sleep disturbances in patients suffering from PTSD, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0709] Improvement in sleep disturbances in patients suffering from PTSD (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from PTSD (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0710] In an embodiment, improvement in sleep disturbances in patients suffering from PTSD (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 until at least 14 days, more preferably until at least 28 days.

[0711] Reduction or elimination of sleep disturbances in patients suffering from PTSD is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] Reduction or elimination of sleep disturbances in patients suffering from PTSD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from PTSD (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0713] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from PTSD (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0714] As mentioned above, sleep disturbance is an important aspect of PTSD. Therefore, improving sleep disturbance will also lead to improvement in PTSD. In addition, because sleep disturbance can also affect other aspects of PTSD, the inventors concluded that improving sleep disturbance, especially reducing or eliminating sleep loss, will additionally contribute to the overall improvement of PTSD.

[0715] Improvements in PTSD in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28.

[0716] Improvement in PTSD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PTSD (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0717] In an embodiment, improvement in PTSD in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S score) is observed as early as 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0718] pain disorders

[0719] Sleep disturbances are common in patients with pain and are associated with chronic pain.

[0720] Chronic pain, also called persistent pain, is long-term pain that persists beyond the normal recovery period (for example, after an injury or surgery) despite medication or treatment. Patients may also develop chronic pain without any obvious cause, such as a history of injury or surgery.

[0721] The prevalence of insomnia (defined as dissatisfaction with the quantity or quality of sleep, difficulty falling asleep, staying asleep, or waking up early) in chronic pain populations is almost twice as high as in the general population, estimated at 24%-32%.

[0722] When sleep disturbances are defined using polysomnography, actinography, or self-report measures, the prevalence estimates rise to 40%-80% in chronic pain patients.

[0723] The relationship between sleep disturbance and chronic pain is thought to be bidirectional, but insomnia may later develop into a separate disorder requiring directly targeted treatment. Other disorders associated with sleep disturbance, such as depression and anxiety, are highly prevalent in the chronic pain population.

[0724] The association between sleep disturbance and chronic pain is also reflected in, for example, the Brief Pain Inventory-Short Form (BPI-sf), a nine-item self-administered questionnaire that assesses the severity of a patient's pain and the impact of this pain on their daily functioning. One item on the BPI-sf is sleep. The questionnaire inquires about the degree to which pain interfered with sleep over the past 24 hours. Therefore, sleep disturbance is a relevant aspect of chronic pain.

[0725] Patients with chronic pain exhibit functional and structural brain alterations. These changes are associated with the persistence of pain, persisting long after the initial noxious input has subsided. Resting-state functional magnetic resonance imaging reveals alterations in distinct regions within and / or across the default mode network, somatomotor / sensorimotor networks, and salience networks.

[0726] Treatment of patients suffering from chronic pain and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement in the chronic pain.

[0727] Reduction or elimination of sleep disturbances in patients suffering from chronic pain is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0728] Reduction or elimination of sleep disturbances in patients suffering from chronic pain occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from chronic pain preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0729] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from chronic pain is observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0730] Improvements in sleep disturbances in patients suffering from chronic pain, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0731] Improvement in sleep disturbances in patients suffering from chronic pain (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from chronic pain (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0732] In an embodiment, improvement in sleep disturbances in patients suffering from chronic pain (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 until at least 14 days, more preferably until at least 28 days.

[0733] Reduction or elimination of sleep disturbances in patients suffering from chronic pain is reflected in an improvement in the Pittsburgh Sleep Quality Index (PSQI) overall score, particularly a decrease in the overall score to 5 or less, on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0734] Reduction or elimination of sleep disturbances in patients suffering from chronic pain (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from chronic pain (as reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0735] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from chronic pain (reflected by an improvement in the PSQI score, particularly a decrease in the score to 5 or below) is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0736] As mentioned above, sleep disturbance is an important aspect of the disease in patients with chronic pain. Therefore, improvement of sleep disturbance will also lead to improvement of chronic pain. In addition, because sleep disturbance can also affect other aspects of chronic pain, the inventors have concluded that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of chronic pain.

[0737] Improvements in chronic pain in patients who also suffer from associated sleep disturbances, as reflected in a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0738] Improvement in chronic pain (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in chronic pain (as reflected in a decrease in CGI-S scores) in patients who also suffer from an associated sleep disorder preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0739] In an embodiment, improvement in chronic pain in patients who also suffer from an associated sleep disorder (reflected by a decrease in CGI-S score) is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0740] Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain throughout the body or in multiple locations, accompanied by fatigue, sleep disturbances, memory, and mood problems. Patients may also experience muscle and joint stiffness, tenderness, numbness or tingling in the arms and legs, difficulty concentrating, thinking clearly, and memory loss (sometimes called "fibro fog"), increased sensitivity to light, noise, smells, and temperature, or digestive problems such as bloating or constipation.

[0741] Studies have shown that people with fibromyalgia have a heightened sensitivity to pain, causing them to feel pain when others don't.

[0742] Sleep problems and fatigue are common symptoms of fibromyalgia. Insomnia, non-restorative sleep, and fatigue are often used as markers for fibromyalgia diagnosis. People with fibromyalgia may also experience restless legs syndrome.

[0743] Sleep disturbances in fibromyalgia can be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0744] There is a bidirectional relationship between fibromyalgia and sleep disturbances. Pain symptoms prevent patients from getting enough rest, while lack of sleep can lower pain thresholds and increase the perception of pain and tenderness.

[0745] The interaction of pain, fatigue, and poor sleep quality often affects patients' ability to function at home or work.

[0746] Previous treatment of fibromyalgia was symptomatic.

[0747] Brain imaging and other studies have found evidence that people with fibromyalgia experience altered signaling in the neural pathways that transmit and receive pain. These changes may also contribute to the fatigue, sleep disturbances, and cognitive problems that many people with the disorder experience.

[0748] Resting-state functional magnetic resonance imaging in patients with fibromyalgia revealed altered functional connectivity within and / or between the DMN and executive attention networks, as well as between the DMN and the insular cortex, a brain region known to process evoked pain.

[0749] Treatment of patients suffering from fibromyalgia and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and results in improvement of the fibromyalgia.

[0750] Reduction or elimination of sleep disturbances in patients suffering from fibromyalgia is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0751] Reduction or elimination of sleep disturbances in patients suffering from fibromyalgia occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of sleep disturbances in patients suffering from fibromyalgia preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0752] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia is observed as early as day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists until at least 14 days, more preferably until at least 28 days.

[0753] Improvements in sleep disturbances in patients suffering from fibromyalgia, as reflected by a decrease in CGI-S scores, are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0754] Improvement in sleep disturbances in patients suffering from fibromyalgia (as reflected by a decrease in CGI-S scores) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in sleep disturbances in patients suffering from fibromyalgia (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0755] In an embodiment, improvement in sleep disturbances in patients suffering from fibromyalgia (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 until at least 14 days, more preferably until at least 28 days.

[0756] Reduction or elimination of sleep disturbances in patients suffering from fibromyalgia is reflected in an improvement in the Pittsburgh Sleep Quality...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients suffering from sleep disorders.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the sleep disorder is insomnia.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the sleep disorder is excessive sleep.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the sleep disorder is a circadian rhythm disorder.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the sleep disorder is parasomnia.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the sleep disorder is sleep-related breathing disorder.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the sleep disorder is sleep-related movement disorder.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 7, wherein the sleep disorder is idiopathic sleep disorder.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from a psychiatric or neurological disorder associated with the sleep disturbance.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 9, wherein the patient suffering from a psychiatric or nervous system disorder suffers from a treatment-resistant form of the disorder.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from a disorder characterized by a depressive episode associated with the sleep disturbance.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 11, wherein the patient suffering from a disorder characterized by a depressive episode suffers from a treatment-resistant form of the disorder.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from major depressive disorder (MDD) associated with the sleep disturbance.

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

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from postpartum depression (PPD) associated with the sleep disorder.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 15, wherein the patient suffering from PPD suffers from a treatment-resistant form of the disorder.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 15 or 16, wherein the patient also suffers from impaired maternal function.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 17, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 80 or less, such as 65 or less.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 17 or 18, wherein said treatment improves maternal function.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 19, wherein said improvement in maternal function is reflected in an improvement in the BIMF total score of 10% or more, preferably 20% or more.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 19 or 20, wherein said improvement in maternal function is reflected at least in an improvement in the BIMF total score at day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 19 or 20, wherein said improvement in maternal function occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected at least in an improvement in the BIMF total score, and wherein said improvement in maternal function persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected at least in an improvement in the BIMF total score.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from bipolar disorder associated with the sleep disturbance.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the patient suffers from bipolar II disorder associated with the sleep disturbance.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the patient suffers from bipolar disorder type I associated with the sleep disturbance.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 23 to 25, wherein the patient suffers from a current major depressive episode.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 23 to 26, wherein the patient suffering from bipolar disorder suffers from a treatment-resistant form of the disorder.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from seasonal affective disorder associated with the sleep disturbance.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 28, wherein the patient suffering from seasonal affective disorder suffers from a treatment-resistant form of the disorder.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from persistent depressive disorder associated with the sleep disturbance.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 30, wherein the patient suffering from persistent depressive disorder suffers from a treatment-resistant form of the disorder.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from an anxiety disorder associated with the sleep disturbance.

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

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from separation anxiety disorder associated with the sleep disturbance.

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

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from agoraphobia associated with the sleep disorder.

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

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from generalized anxiety disorder (GAD) associated with the sleep disturbance.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 38, wherein the patient suffering from GAD suffers from a treatment-resistant form of the disorder.

40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from social anxiety disorder (SAD) associated with the sleep disturbance.

41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 40, wherein the patient suffering from SAD suffers from a treatment-resistant form of the disorder.

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from panic disorder associated with the sleep disturbance.

43. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 42, wherein the patient suffering from panic disorder suffers from a treatment-resistant form of the disorder.

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from a phobia associated with the sleep disorder.

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

46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from a substance / medication induced anxiety disorder associated with the sleep disturbance.

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 46, wherein the patient suffering from substance / medication induced anxiety disorder suffers from a treatment resistant form of the disorder.

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from somatic symptom disorder associated with the sleep disturbance.

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

50. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from obsessive compulsive disorder or a related disorder associated with the sleep disturbance.

51. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 50, wherein the obsessive compulsive disorder or related disorder is obsessive compulsive disorder (OCD).

52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 50 or 51, wherein the patient suffers from a treatment-resistant form of the disorder.

53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from body dysmorphic disorder (BDD) associated with the sleep disturbance.

54. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 53, wherein the patient suffering from BDD suffers from a treatment-resistant form of the disorder.

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from post-traumatic stress disorder (PTSD) associated with the sleep disturbance.

56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 55, wherein the patient suffering from PTSD suffers from a treatment-resistant form of the disorder.

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from a pain disorder associated with the sleep disturbance.

58. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 57, wherein the patient suffers from chronic pain associated with the sleep disorder.

59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 57 or 58, wherein the patient suffers from a treatment-resistant form of the disorder.

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from fibromyalgia associated with the sleep disorder.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from migraine associated with the sleep disorder.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from psychiatric and behavioral disorders due to the use of psychoactive substances associated with the sleep disturbance.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 62, wherein the patient suffers from a substance use disorder (SUD) associated with the sleep disturbance.

64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 62 or 63, wherein the patient suffers from a treatment-resistant form of the disorder.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from a psychotic disorder associated with the sleep disturbance.

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

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from schizophrenia associated with the sleep disorder.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 67, wherein the patient suffering from schizophrenia suffers from a treatment-resistant form of the disorder.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from Huntington's disease associated with the sleep disorder.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from Parkinson's disease associated with the sleep disorder.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from dementia associated with the sleep disorder.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from Alzheimer's disease dementia associated with the sleep disorder.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from Parkinson's disease dementia associated with the sleep disorder.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from Lewy body dementia associated with the sleep disorder.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from vascular dementia associated with the sleep disorder.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from frontotemporal dementia associated with the sleep disorder.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from an eating disorder associated with the sleep disturbance.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 77, wherein the patient suffering from an eating disorder suffers from a treatment-resistant form of the disorder.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from attention deficit hyperactivity disorder (ADHD) associated with the sleep disorder.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 79, wherein the patient suffering from ADHD suffers from a treatment-resistant form of the disorder.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from a personality disorder associated with the sleep disturbance.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 81, wherein the patient suffers from schizotypal personality disorder associated with the sleep disturbance.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 81 or 82, wherein the patient suffers from a treatment-resistant form of the disorder.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from borderline personality disorder (BPD) associated with the sleep disturbance.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 84, wherein the patient suffering from BPD suffers from a treatment-resistant form of the disorder.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from autism spectrum disorder (ASD) associated with the sleep disturbance.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient suffers from chronic fatigue syndrome associated with the sleep disorder.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 87, wherein the patient suffering from chronic fatigue syndrome suffers from a treatment-resistant form of the disorder.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the sleep disorder is due to traumatic brain injury.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the sleep disorder is due to HIV infection.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 1, wherein the sleep disorder is due to COVID sequelae.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 91, wherein said treatment reduces or eliminates said sleep disturbance.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 92, wherein said reduction or elimination of sleep disturbances is observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 92, wherein said reduction or elimination of sleep disturbances occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein said reduction or elimination of sleep disturbances lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 92, wherein said reduction or elimination of sleep disturbances is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably lasts until at least 14 days, more preferably until at least 28 days.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 9 to 95, wherein said treatment results in improvement of said diagnosed disorder in a patient who also suffers from an associated sleep disorder.

97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 96, wherein the improvement in the diagnosed disorder in patients who also suffer from an associated sleep disorder is observed as a decrease in the Clinical Global Impression - Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 96, wherein said improvement in said diagnosed disorder in a patient also suffering from an associated sleep disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, and wherein said improvement in said diagnosed disorder in a patient also suffering from an associated sleep disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 96, wherein said improvement of said diagnosed disorder in a patient also suffering from an associated sleep disorder is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, and preferably persists until at least 14 days, more preferably until at least 28 days.

100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 99, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 100, wherein a dosage of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 100, wherein a dose of about 6 mg; or about 12 mg; or about 18 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 101, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 103, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg for a first administration, then increased to a dose of about 8 mg to about 14 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 104, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 103 to 105, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 100 to 106, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 107, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 108, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation, or by nasal, buccal or sublingual administration.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 109, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol, the aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as to about 12.5 mg / l.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 110, wherein the aerosol is generated by: a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer to produce aerosol particles.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 109 to 111, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled via a single breath.

113. 5-MeO-DMT for use as claimed in claims 109 to 112, wherein the 5-MeO-DMT is used in the form of a free base.

Images