5-MeO-DMT for treatment of sleep disorders

Abstract

5-methoxy-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 wherein the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is administered via the intravenous, intramuscular or subcutaneous route.

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 disorders; obsessive-compulsive disorder and related disorders, for example, obsessive-compulsive disorder (OCD) and body dysmorphic disorder. Disorder (BDD); 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, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; psychiatric or neurological disorders related to HIV, traumatic brain injury, or 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 (sleep disorders) are conditions that affect the quality, timing, or duration of sleep. Sleep disturbances 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, for example, a psychiatric disorder or a 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] One object of the present invention is, in particular, 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, which 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, which 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, which are associated with higher patient compliance rates (including higher treatment initiation rates) 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 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 disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); trauma 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, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; psychiatric or neurological disorders related to HIV, traumatic brain injury, or COVID sequelae.

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

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

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

[0015] definition

[0016] 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 from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. Assuming that equimolar amounts are used, the appropriate weight of the salt to be administered can be calculated based on the weight of the free base.

[0017] 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 sleep disorder may or may not be part of the diagnosis.

[0018] 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 apparent from the discussion of specific circumstances below, it is possible to modify or supplement the standard to better define a patient or patient population that is particularly benefited from treatment according to the present invention. In any case, the diagnosis will be carried out by a doctor or psychologist. It is not enough for the human subject himself to believe that he suffers from the disorder.

[0019] 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, illness or disorder, and includes 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, illness or disorder.

[0020] "Treatment of sleep disorders" shall include the management and care of patients for the purpose of combating sleep disorders, and includes the administration of 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 disorders or neurological disorders.

[0021] The patient may suffer from a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. The patient has not adequately improved after at least two adequate courses of treatment, in particular, at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy. In particular, at least two prior courses of treatment were administered during the current episode of the disease, for example, if the patient suffers from a disorder characterized by a depressive episode, during the current depressive episode.

[0022] 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 being that is being sought by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0023] "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.

[0024] The severity of the disorder, as well as changes in severity, can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and efficacy of treatment.

[0025] 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).

[0026] 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 the patient currently?” Rated on a seven-point scale: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat severely ill; 6 = severely ill; and 7 = the sickest patient.

[0027] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0028] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), 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 inquiry rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this 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."

[0029] 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 disease severity (PGI-S) or disease improvement (PGI-I).

[0030] Individual items as well as subcombinations of individual items of the scales as described herein can be used to assess specific disease aspects.

[0031] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. The active compound is administered by intravenous administration, intramuscular administration or subcutaneous administration.

[0032] As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "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 order of one or more separate administrations.

[0033] Sleep disturbances

[0034] 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 depth of sleep. 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.

[0035] Normal, healthy sleep consists of the different stages described above, which proceed in a continuous, strictly controlled sequence throughout the night.

[0036] Disruptions in this tight control can lead to sleep disturbances.

[0037] Sleep disturbance refers to a condition that affects the quality, timing or duration of sleep, whether idiopathic or occurring in the context of a medical condition such as, for example, a psychiatric disorder or a neurological disorder. Sleep disturbance affects a person's ability to function normally while awake.

[0038] 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).

[0039] Insomnia is a sleep disorder in which the patient has difficulty falling asleep or staying asleep. People with insomnia have trouble falling asleep; wake up frequently during the night and have difficulty 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, accidents at work or while driving, etc.

[0040] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomniacs. Transitioning from sleep to wakefulness is difficult. Individuals who experience sleep drunkenness report being confused, disoriented, sluggish, and falling asleep again and again upon awakening.

[0041] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances due to alterations in an individual's internal circadian rhythm or due to inconsistencies between their circadian rhythm and their desired or required work or social schedules. This desynchronization may be temporary or persistent. The ensuing clinical presentation combines symptoms of insomnia and hypersomnia. Sleep duration is often shortened and interrupted, performance in the desired wakefulness state is impaired, and restoration of a normal sleep schedule is temporarily impossible.

[0042] Parasomnias refer to various forms of sleep disorders characterized by people experiencing unusual behaviors or physiological activities (such as sleepwalking or nightmares) before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias may impair sleep quality.

[0043] 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 when the brain stops sending signals to control breathing, for example, 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 hypoxia, which causes sleep fragmentation due to micro-arousals or awakenings. The consequence can be excessive daytime sleepiness.

[0044] 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).

[0045] Insufficient sleep duration or quality may lead to personality changes and may not only exacerbate existing mental illnesses, but may also be a contributing factor to their development. Sleep disturbances may also interfere with cognitive function and lead to memory impairment. Sleep-deprived subjects may experience difficulty in decision-making, irritability, poor performance, and may have slower reaction times. Insufficient sleep can also adversely affect life by contributing to the development of obesity, diabetes, and heart disease.

[0046] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatment may involve medication or psychotherapy.

[0047] 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.

[0048] In patients suffering from sleep disturbances associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorders do not necessarily improve the sleep disturbances.

[0049] For example, sleep disturbances are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of 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 sleep impairment.

[0050] Measuring sleep disturbances

[0051] 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).

[0052] Polysomnography is a technique that requires patients to be monitored 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.

[0053] Another quantitative measurement 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.

[0054] 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 about 10 minutes is considered normal; less than eight minutes indicates a sleep disorder (excessive daytime sleepiness). An accompanying analysis of brain activity can help further diagnose a sleep disorder.

[0055] The sleep rating questionnaire captures ratings of components of sleep quality, such as perception of sleep depth, difficulty in waking, and rest after sleep, as well as other factors that may affect sleep quality, such as comorbidities and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep discomfort may often persist despite normal values ​​for quantitative sleep measures.

[0056] Questionnaires not only facilitate rapid and accurate assessment of complex clinical problems but may also be useful in tracking the patient's progress.

[0057] 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.

[0058] 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 treatments, especially those that start 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 article discusses questionnaires for assessing the effects of treatment on sleep in patients suffering from specific conditions, which rely on a recall period that starts no earlier than the time point when the acute psychedelic experience subsides after the last administration. In order to meet this criterion, the normally applied recall period is modified if necessary.

[0059] For example, the Sleep-50 questionnaire can be used to assess general sleep quality.

[0060] The Sleep-50 questionnaire consists of 50 items, which are designed to screen various sleep disorders in the general population. The scale consists of nine subscales, reflecting some of the most common disorders and discomforts associated with sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily function. For each item, the respondent will get a scale from 1 ("not at all") to 4 ("very much"), and is asked to indicate the degree of match between the statement and their experience in the last month or another appropriate recall window.

[0061] 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 lot" or "very much", respectively) on a subscale assessing 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).

[0062] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0063] A commonly used questionnaire to assess sleep disturbance is the Pittsburgh Sleep Quality Index. Other tools are the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System (PRIME). )Sleep disorders.

[0064] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-rating questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

[0065] Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. The 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.

[0066] Each component is scored from 0 to 3. Higher scores indicate more severe sleep disturbance. A detailed scoring description of 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.

[0067] The seven component scores are then summed to create an overall score ranging from 0-21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas, or moderate difficulty in more than three areas.

[0068] 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.

[0069] The Insomnia Severity Index (ISI) is a short questionnaire that relates to subjective sleep quality, severity of symptoms, subjective satisfaction with sleep, degree of interference of insomnia with daily functioning, how significant the respondent feels their insomnia is compared to other people, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (=none) to 4 (=very); higher total scores correspond to more severe insomnia. Total scores of 0-7 represent "no clinically significant insomnia", 8-14 mean "subthreshold insomnia", 15-21 are "clinical insomnia (moderate severity)", and 22-28 mean "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.

[0070] Treatment success is indicated by (i) a decrease in the score, for example a decrease of >7 points, particularly >8 points; preferably (ii) a decrease in the score to below the cut-off value for clinically significant insomnia.

[0071] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ rates restlessness / agitation, mental overactivity, consequences of insomnia, and lack of sleep preparation, 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 experiences. 1 means "never true," and 5 means "often true." The higher the score, the more abnormal the belief in the causes and associated factors of insomnia (A. Shahid et al., supra).

[0072] A decrease in the score indicates successful treatment.

[0073] Patient Reported Outcomes Information System The Sleep Disturbance Tool is a general method for assessing sleep disturbances. The tool has one 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 related to falling asleep and staying asleep over a 7-day period.

[0074] Each item in the measure is rated on a 5-point scale. The raw scores of the items are summed to obtain a total raw score. The total raw score is then converted to a standardized T score using a conversion table.

[0075] A decrease in T score indicates successful treatment.

[0076] Excessive sleeping or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0077] The Epworth Sleepiness Scale (ESS) evaluates overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, which represent 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 means "never doze off," and 3 means "very likely doze off"). The scoring range is 0-24; the higher the score, the higher 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).

[0078] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 10 or less.

[0079] 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 sleepiness level. The sleepiness level is assessed using a scale from 1 (=feeling active and energetic; alert; fully awake) to 7 (=almost in a trance; falling asleep quickly; unable to stay awake) (A. Shahid et al., supra).

[0080] A decrease in the score indicates successful treatment.

[0081] Parasomnias can be assessed using the Paris Arousal Disorders Severity Scale (PADSS).

[0082] 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).

[0083] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0084] A commonly used questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period may also be selected.

[0085] A decrease in the score indicates successful treatment.

[0086] The commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The questionnaire of the 10 items requires the respondents to use the Likert-type rating method to indicate how serious the impact of this disorder on them has been in the past week. The problem can be divided into one of two categories: disorder symptoms (nature, intensity and frequency) and their impact (sleep problems, daily functional disorders and resulting mood changes). Each of the ten questions requires the respondents to rate their RLS experience with a scale of 0 to 4, wherein 4 represents the most serious and most frequent symptoms, and 0 represents the least symptoms. The total score range can be 0 to 40. As a concise scale with excellent psychometric quality, the tool can be applied to a variety of research and clinical purposes, including screening and evaluating treatment outcomes. (A. Shahid et al., supra).

[0087] The response to treatment can be assessed by a decrease in the score.

[0088] Scales for the assessment of mental and neurological disorders

[0089] A variety of scales have been proposed to assess the severity of psychiatric or neurological disorders. Such scales are based on tests that can be self-administered or administered by a clinician.

[0090] 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.

[0091] Treatment outcomes are assessed by using one or more indices or scales at one or more time points after completion of the course of treatment.

[0092] 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 generally be performed, for example, about 2 hours or about 3 hours after the last administration.

[0093] However, assessment of sleep disrupting effects or effects on psychiatric or neurological disorders associated with sleep disrupting effects 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.

[0094] 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.

[0095] Assessment on 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.

[0096] For example, when one of the scales is used to assess the severity of a mental or nervous system disorder, when evaluating clinical response at an early time point (e.g., 2 hours) after drug administration based on an endpoint developed for a longer recall period (e.g., MADRS is typically 7 days), such endpoints can be reasonably modified (e.g., changing the MADRS recall period to 2 hours and carrying forward the sleep items recorded at baseline before drug administration). Unless a recall period is specifically specified, the same applies to any other scale used herein to assess the therapeutic effect of a mental or nervous system disorder.

[0097] The considerations outlined apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment 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.

[0098] At a later time point, such as on day 1 or later, all items of the relevant scales used to assess clinical response can generally be assessed with an appropriate recall period (if necessary) so that no pre-treatment scores need to be carried forward.

[0099] Resting-state networking and sleep disturbances

[0100] Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0101] Functional images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

[0102] 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).

[0103] 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.

[0104] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0105] RSNs have been shown to be responsible for various aspects of complex brain function, and these networks of connectivity have been found to be impaired in various disease states.Such disease states are associated with altered functional connectivity within a specific resting-state network and / or between one or more regions in one or more additional resting-state networks.

[0106] Altered resting-state networks can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0107] A key network involved in sleep is the default mode network (DMN). In general, the DMN is deactivated during tasks and activated during rest. It is involved in a variety of cognitive processes, such as higher-order cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, altered DMN activity is particularly relevant to sleep disorders.

[0108] 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 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); and post-traumatic stress disorder. post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraine; 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, 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 related to HIV, traumatic brain injury, or COVID sequelae.

[0109] Resting-state networks involved in disrupted sleep can also be affected by psychiatric or neurological disorders resulting from certain medical health conditions.

[0110] In patients with insomnia, functional connectivity impairments were observed within the default mode network (DMN) and within 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 the integration of emotional and physical states, and that functional connectivity impairments within and / or between these networks and other brain regions may account for patients' alertness, subjective distress, and poor sleep continuity.

[0111] 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 in the DMN is associated with self-reported severity of sleepiness.

[0112] A study investigating differences between night-shift nurses and day-shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, involved in sleep regulation and cognitive functions such as responsiveness and alertness. In addition, functional connectivity of the DMN is fundamentally different in early and late circadian rhythm phenotypes. As with other forms of sleep disturbance, circadian rhythm disturbances can lead to changes in brain functional connectivity. Changes in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disturbances.

[0113] Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders representative of non-REM parasomnias.

[0114] The precuneus is involved in the analysis and integration of visual, auditory and somatosensory information and the monitoring of movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnias, the default mode network is affected.

[0115] 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.

[0116] 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. In addition, activity in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem, could be observed.

[0117] In many cases, abnormal functional connectivity of resting state networks associated with sleep disturbances are also associated with the above-mentioned disorders. Therefore, according to the present invention, influencing these 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 disorder or a neurological disorder, also to an improvement in said disorder.

[0118] Active Agent

[0119] The above discussion shows that sleep disturbance itself carries a significant disease burden and should be treated appropriately.

[0120] The inventors believe that carefully selected hallucinogens may lead to treatments that improve important aspects of sleep disorders, and may lead to overall improvement of the disorder.

[0121] A group of hallucinogens consists of 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 called "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

[0122] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, of which the indoleamines are divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

[0123] 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-associated receptors.

[0124] Recently published studies using serotonergic psychedelics such as LSD, psilocybin, and DMT (using the shamanic medicine ayahuasca containing DMT) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may hamper their clinical use.

[0125] 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 patient who had a manic episode after taking LSD or LSD analogs. The patient had symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 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 MSmith, 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.

[0126] 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.

[0127] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

[0128] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for use in therapy. 5-MeO-DMT has unique pharmacological properties that are distinct from other psychedelic compounds.

[0129] 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 psychedelics.

[0130] As further detailed in the Examples section below, the inhibition constants (K) for psilocin (the dephosphorylated form of psilocybin formed following ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin dephosphate, 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 moderate affinity. i values) were 37, 117, and 122 nM, respectively. Thus, dephosphorylated psilocybin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0131] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

[0132] 5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0133] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing 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 disorder type I and bipolar disorder type 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.

[0134] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0135] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

[0136] Further, it has been reported that antidepressants induce isolated hypomanic episodes in patients suffering from 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 inducing hypomania.

[0137] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to, for example, several hours with 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.

[0138] 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, [ 3 H]LSD and serotonin to estimate nonspecific binding and determine K i 2.3 nM. 5-HT7 receptors play a role in neurogenesis, synaptogenesis and dendritic spine formation.

[0139] Another characteristic of 5-MeO-DMT is its short half-life.

[0140] 5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0141] 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 dosing.

[0142] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0143] 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.

[0144] The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

[0145] According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used.When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0146] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0147] A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

[0148] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0149] 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-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

[0150] 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.

[0151] Methods for the preparation of these compounds are known in the art.

[0152] 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.

[0153] 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.

[0154] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

[0155] In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0156] 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.

[0157] 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.

[0158] Prodrugs, especially prodrugs of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0159] 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).

[0160] Methods for preparing prodrugs as discussed herein are known in the art.

[0161] According to the present invention, the T of the metabolite 5-MeO-DMT measured after oral administration of the prodrug at 10 mg / kg in male Sprague-Dawley (SD) rats max The value is preferably 1 hour or less, more preferably 0.7 hour or less, particularly 0.5 hour or less.

[0162] 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.

[0163] Mode of administration

[0164] Therapeutically effective amounts of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., administration by intravenous injection.

[0165] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration via injection, and examples of excipients and vehicles for such formulations are known in the art.

[0166] Dosage regimen

[0167] The present invention also provides dosage ranges, specific dosages and dosing regimens (administration regimens) and appropriate administration routes.

[0168] The present invention is based in part on the inventors' conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, which drives the therapeutic benefit of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, in patients suffering from sleep disorders, particularly one or more aspects as defined above, either causally or at least as a surrogate behavioral marker of a potential unknown therapeutic mechanism.

[0169] Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility in individual patients will result in a better therapeutic profile than previously tested psychedelics, dosing regimens, and routes of administration.

[0170] Furthermore, the present invention also 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 physical 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 the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0171] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be achieved with other psychedelics due to the late onset and prolonged duration of the psychedelic effects and due to the rapid development of tolerance (i.e., the psychedelic effects diminish or disappear upon re-administration), which may persist for several days.

[0172] A patient suffering from a sleep disorder as defined herein is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0173] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other sleep disorder treatment.

[0174] The dosage range of 5-MeO-DMT administered to a patient suffering from a sleep disorder as defined herein is from about 1 mg to about 10 mg, or any range therein, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated based on the specified weight of 5-MeO-DMT free base assuming the use of equimolar amounts. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Please note that in this specification, when a range is listed (such as "about 1 mg to about 10 mg"), the inventors consider all discrete values ​​within the range, some of which are explicitly mentioned, but not all of them - this is only for the purpose of brevity.

[0175] In a preferred embodiment, 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.

[0176] In preferred embodiments, improved methods of treating patients suffering from a sleep disorder 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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 is 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 is no less than about 6 days.

[0181] In embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0182] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until reaching 10 mg, or all administrations within that treatment block have been administered, whichever is earlier.

[0183] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

[0184] For embodiments in which the dose of a subsequent administration is increased, the dose of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dose of the previous administration. For example, if the first administration dose is 1 mg and the dose increase is 3 mg, the second administration dose is 4 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administration dose is 7 mg.

[0185] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg at the first administration, and then increased to a dose selected from about 4 mg to about 6 mg at the second administration, and to a dose selected from about 7 mg to about 9 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0186] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg at the first administration, and then increased to a dose selected from about 1.5 mg to about 2.5 mg at the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0187] 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 1 mg to about 2 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 8 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 8 mg.

[0188] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 1 mg to about 3 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration in the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0189] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 0.5 mg to about 1.5 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 1.5 mg to about 2.5 mg, and the third administration in the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0190] It will be appreciated that a pharmaceutically acceptable salt of 5-MeO-DMT is preferred for all of the above dosing regimens and that, assuming equimolar amounts are used, the appropriate weight of salt to be administered can be calculated based on the specified weight of the free base.

[0191] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0192] Patients 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).

[0193] Whether a patient has a “peak psychedelic experience” can also be determined by achieving at least 60% of the maximum possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0194] According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 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?

[0195] Treatment of sleep disorders and psychiatric and neurological disorders

[0196] 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 the improvement of the diseases associated with sleep disorders.

[0197] In many cases, resting-state networks associated with sleep disturbances are also implicated in the above disorders.

[0198] 5-MeO-DMT is able to interrupt established functional connectivity patterns of resting-state networks. This disruption results in a reset of pathological, poorly connected brain connections as the network rewires. New, healthy functional connections are established, and this has a lasting effect.

[0199] The neuroplasticity-promoting properties of 5-MeO-DMT may explain the persistence of this effect. 5-MeO-DMT specifically promotes structural and functional plasticity at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT modulates the morphogenesis and maturation of dendritic spines, thereby initiating the formation of new synaptic connections. These new connections will be strengthened, weakened, or even eliminated depending on activity.

[0200] The resulting new synapses in turn affect the activity patterns of neurons. The inventors conclude that such reciprocal structural and functional modifications contribute to the proper establishment of networks and the persistence of effects following administration of 5-MeO-DMT.

[0201] From a biochemical point of view, 5-MeO-DMT interacts with, among other things, the 5-HT receptor.

[0202] 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.

[0203] In the brain, seven types of 5-HT receptors are expressed, which can be further divided into several subtypes. The various types and subtypes exhibit different spatial distributions.

[0204] 5-MeO-DMT interacts with several 5-HT receptors. These receptors are implicated in mediating the effects of 5-MeO-DMT on resting-state networks and neural plasticity.

[0205] In addition to 5-HTAl and 5-HT2A discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0206] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0207] 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.

[0208] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0209] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0210] The inventors believe that the combination of 5-MeO-DMT and 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 the treatment of patients suffering from sleep disorders.

[0211] 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 neuroplasticity effects, 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 shown in the studies mentioned herein.

[0212] 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, will also result in an improvement in said disorder.

[0213] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) demonstrate that sleep disturbances can be successfully treated by administering 5-MeO-DMT.

[0214] In the TRD study described in more detail in the Examples section below, the MADRS item "Sleep reduction" reflecting insomnia was assessed, among others.

[0215] The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the normal pattern of the subject's own health. When the subject's sleep is normal, the score is 0. A score of 2 reflects mild difficulty falling asleep, or slightly reduced, shallow or intermittent sleep time. A score of 4 means that sleep time is reduced or interrupted by at least two hours. A score of 6 means less than two or three hours of sleep.

[0216] In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

[0217] In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 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%.

[0218] Thus, 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 psychiatric disorders or nervous system disorders.

[0219] Idiopathic sleep disorders

[0220] 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.

[0221] Reduction or elimination of idiopathic sleep disturbance 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.

[0222] The reduction or elimination of idiopathic sleep disturbance preferably 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 idiopathic sleep disturbance 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.

[0223] In an embodiment, reduction or elimination of idiopathic sleep disturbance 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.

[0224] In the case of idiopathic sleep disorders, the clinical response can 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 is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and / or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and / or to 0 points.

[0225] Improvement in idiopathic sleep disturbance (reflected by a decrease in CGI-S score) is observed on day 1, e.g., about 24 hours after; 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.

[0226] Improvement in idiopathic 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.

[0227] The improvement of idiopathic sleep disturbance (reflected by a decrease in CGI-S score) 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.

[0228] In an embodiment, improvement in idiopathic sleep disturbance (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.

[0229] In the case of idiopathic sleep disorders, improvement in sleep disorders (at least as reflected by a score of "much improved" in 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 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.

[0230] Improvement in idiopathic sleep disturbance (at least as reflected 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.

[0231] The improvement in sleep disturbance (at least as reflected by a score of "much improved" in 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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0232] In an embodiment, improvement in idiopathic sleep disturbance (at least as reflected by a score of "much improved" in the CGI-I score or the PGI-I 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.

[0233] Improvement in idiopathic sleep disturbance 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).

[0234] If the PSQI is used to assess treatment outcome, treatment success is indicated by (i) a decrease in the total score, preferably (ii) a decrease in the total 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.

[0235] Improvement in idiopathic sleep disturbance (as reflected by a decrease in PSQI-S total score, particularly a decrease 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.

[0236] Such improvement in idiopathic sleep disturbance (reflected by a decrease in the PSQI-S total score, in particular a decrease to 5 or below) 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.

[0237] 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 below.

[0238] In an embodiment, improvement in idiopathic sleep disturbances is observed on day 7, as reflected by a decrease in the PSQI total score, in particular a decrease in the total score to 5 or below, and preferably persists until day 14, more preferably until day 28.

[0239] Sleep disturbances associated with psychiatric and neurological disorders

[0240] Although disrupted sleep may be considered a condition that should be treated independently of any other condition, disorder, or symptom 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 be a contributing factor to the onset, progression, and prognosis of mental health or neurological disorders.

[0241] The treatment method according to the present invention can reduce or eliminate sleep disturbances, and preferably also improve related psychiatric or neurological disorders.

[0242] Disorders characterized by depressive episodes

[0243] Several disorders are characterized by depressive episodes.

[0244] A depressive episode is a period of depressed mood and / or loss of interest in most activities.

[0245] 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.

[0246] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0247] During a depressive episode, people often suffer from insomnia or excessive sleeping.

[0248] 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 test.

[0249] Montgomery-Asberg Depression Rating Scale ( The MADRS (Madrid Depression Rating Scale) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0250] 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.

[0251] The item sleep reduction reflects the experience of disturbed sleep, especially reduced duration or depth of sleep, compared to the normal pattern of the subject's own health. If the patient's sleep is normal, the score is 0. If the patient has slight difficulty falling asleep, or the sleep time is slightly reduced, shallow, or intermittent, the score is 2. If the sleep time is reduced or interrupted for at least two hours, the score is 4. In the case of less than two or three hours of sleep, the score is 6.

[0252] The Hamilton Rating Scale for Depression (HAM-D) can help clinicians assess the nature and severity of mood disturbances in a patient population. The scale consists of 21 items, but only the first 17 items (depressed mood; guilt; suicidality; initial insomnia; nighttime insomnia; delayed insomnia; work and interest; retardation; agitation; mental anxiety; physical anxiety; gastrointestinal somatic symptoms; general somatic symptoms; genital symptoms; hypochondriasis; weight loss; insight) are used for scoring.

[0253] For most questions, the score range is 0 to 4, with 4 representing 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 can be contrasted to a predefined cutoff score.

[0254] Initial insomnia reflects insomnia early in the night. It is scored as 0 if the patient has no difficulty falling asleep, 1 if the patient complains of occasional difficulty falling asleep (ie, more than 1 / 2 hour), and 2 if the patient complains of difficulty staying asleep at night.

[0255] 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 time of getting up, except for the purpose of urinating, was scored as 2).

[0256] 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 falls back asleep, and a score of 2 if the patient is unable to fall asleep again after getting up.

[0257] 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.

[0258] Treatment of patients suffering from a disorder characterized by a depressive episode (including treatment-resistant forms of the disorder) and an associated sleep disturbance with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, reduces or eliminates the sleep disturbance and results in an improvement in the disorder characterized by a depressive episode.

[0259] 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.

[0260] The reduction or elimination of sleep disturbance 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. The reduction or elimination of sleep disturbance 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.

[0261] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a disorder characterized by a depressive episode 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.

[0262] Improvements in sleep disturbances in patients suffering from a disorder characterized by a depressive episode, 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.

[0263] Improvement of sleep disturbance in patients suffering from a disorder characterized by a depressive episode (as reflected by 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 of sleep disturbance in patients suffering from a disorder characterized by a depressive episode (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0264] 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 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.

[0265] 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.

[0266] The reduction or elimination of sleep disturbance (particularly sleep loss) in patients suffering from a disorder characterized by a depressive episode (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 disturbance (particularly sleep loss) in patients suffering from a disorder characterized by a depressive episode (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.

[0267] In an embodiment, a reduction or elimination of sleep disturbances, in particular sleep loss, in patients suffering from a disorder characterized by a depressive episode (reflected as 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.

[0268] 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.

[0269] The reduction or elimination of sleep disturbance (particularly decreased sleep) in patients suffering from a disorder characterized by a depressive episode (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. The reduction or elimination of sleep disturbance (particularly decreased sleep) in patients suffering from a disorder characterized by a depressive episode (reflected by an improvement in the PSQI overall score, particularly a decrease in the overall score to 5 or below) preferably lasts 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.

[0270] In an embodiment, a reduction or elimination of sleep disturbances (particularly decreased sleep) in patients suffering from a disorder characterized by a depressive episode (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.

[0271] 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. In addition, since sleep disturbances also affect other aspects of disorders characterized by depressive episodes, the inventors conclude that improvements in sleep disturbances, particularly reduction or elimination of sleep loss, will additionally contribute to overall improvements in disorders characterized by depressive episodes.

[0272] Improvements in disorders characterized by depressive episodes in patients who also suffer from associated sleep disturbances, 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.

[0273] Improvement of the disorder characterized by depressive episodes in patients who also suffer from associated sleep disturbances (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 of the disorder characterized by depressive episodes in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0274] In an embodiment, improvement in disorders characterized by depressive episodes in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0275] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects a person's feelings, thoughts, and behaviors and can lead to a variety of emotional and physical problems.

[0276] 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. It is further considered that patients may 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.

[0277] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder (TRD).

[0278] In patients with MDD, functional connectivity disturbances 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 was significantly different from that observed in healthy controls.

[0279] As mentioned above, functional connectivity disturbances in resting-state networks are also associated with sleep disorders such as insomnia and hypersomnia.

[0280] An estimated three-quarters of all patients with MDD experience some form of sleep disturbance, such as insomnia or excessive sleepiness, sometimes both at the same time. 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 meet the diagnosis of MDD.

[0281] Sleep disturbance in the setting of MDD is associated with a greater risk of suicide and a significant decrease in patients' quality of life.

[0282] 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.

[0283] A 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.

[0284] The 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. The reduction or elimination of sleep disturbances 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.

[0285] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from MDD 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.

[0286] 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.

[0287] Improvement of sleep disturbances in patients suffering from MDD (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 of sleep disturbances in patients suffering from MDD (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0288] In an embodiment, improvement in sleep disturbances in patients suffering from MDD (reflected by a decrease in CGI-S score) 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.

[0289] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from MDD is reflected at least in an improvement in the score of 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.

[0290] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from MDD (at least 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 MDD (at least 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.

[0291] In an embodiment, a reduction or elimination of sleep disturbances, in particular sleep loss, in patients suffering from MDD (reflected as 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.

[0292] Reduction or elimination of sleep disturbances in patients suffering from MDD 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.

[0293] The reduction or elimination of sleep disturbances in patients suffering from MDD (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. The reduction or elimination of sleep disturbances in patients suffering from MDD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0294] 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 lasts until at least 14 days, more preferably until at least 28 days.

[0295] As mentioned above, sleep disturbance is closely related to MDD. Therefore, improvement of sleep disturbance will also lead to improvement of MDD. In addition, since sleep disturbance will also affect other aspects of MDD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of MDD.

[0296] Improvements in major depressive disorder 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.

[0297] Improvement in major depressive disorder in patients who also suffer from associated sleep disturbances (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 associated sleep disturbances (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; 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, improvement in MDD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0299] Sleep disturbances are also associated with postpartum depression (PPD).

[0300] 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 about 15%.

[0301] 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. Further consideration is given to patients who may 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.

[0302] 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.

[0303] Furthermore, patients treated according to the present invention may have a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0304] Furthermore, patients treated according to the present invention may have a MADRS score of 35 or higher or a HAM-D score of 25 or higher.

[0305] Patients suffering from PPD may suffer from a treatment-resistant form of the disorder.

[0306] Depression during the postpartum period not only affects the mother's overall health, but it also affects the way the mother interacts with her child, which can affect the child's development.

[0307] Sleep disturbance is a common symptom during pregnancy and is 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.

[0308] Sleep disturbance during pregnancy is itself a predictor of PPD.

[0309] The study showed that changes in sleep quality, rather than changes in the hormonal milieu, were associated with PPD recurrence and severity.

[0310] PPD can be assessed by the Edinburgh Postnatal Depression Scale (EPDS), which is used to rate how the mother has felt over the past 7 days. Insomnia due to unhappiness is one of the 10 questions assessed in 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 diagnosis of PPD.

[0311] In patients with PPD, significant changes in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition can be observed. PPD is associated with functional impairments in resting-state networks, such as within and / or between the default mode network and the frontoparietal network.

[0312] 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.

[0313] A 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.

[0314] The 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. The reduction or elimination of sleep disturbances 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.

[0315] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from PPD 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.

[0316] Improvements in sleep disturbances in patients suffering from PPD are observed as reflected in a decrease in CGI-S scores 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.

[0317] Improvement of sleep disturbances in patients suffering from PPD (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 of sleep disturbances in patients suffering from PPD (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0318] In an embodiment, improvement in sleep disturbances in patients suffering from PPD (reflected by a decrease in CGI-S score) 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.

[0319] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from PPD is reflected at least in an improvement in the score of 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.

[0320] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from PPD (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 PPD (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.

[0321] In an embodiment, a reduction or elimination of sleep disturbances, particularly sleep deprivation, in patients suffering from PPD is observed on the 7th day 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.

[0322] Reduction or elimination of sleep disturbances in patients 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 below, 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.

[0323] The reduction or elimination of sleep disturbances in patients suffering from PPD (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. The reduction or elimination of sleep disturbances in patients suffering from PPD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0324] 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 lasts until at least 14 days, more preferably until at least 28 days.

[0325] As mentioned above, sleep disturbance is closely related to PPD. Therefore, improvement of sleep disturbance will also lead to improvement of PPD. In addition, since sleep disturbance will also affect other aspects of PPD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of PPD.

[0326] Improvements in postpartum depression 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.

[0327] Improvement in postpartum depression in patients who also suffer from associated sleep disturbances (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 postpartum depression in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] In an embodiment, improvement in PPD in patients also suffering from associated sleep disturbances (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.

[0329] In an embodiment, improvement in PPD in patients also suffering from associated sleep disturbances, as reflected by improvement in the Edinburgh Postpartum Depression Scale (EPDS), 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.

[0330] In addition, sleep disturbances can impair maternal functioning.

[0331] For example, the Barkin Index of Maternal Function (BIMF) can be used to assess maternal function. The index is designed to measure function within one year after childbirth. The BIMF is a 20-item self-report function measurement. Each item is scored from 0 to 6, making the maximum total score 120 points. The higher the score, the better the assessment of maternal function.

[0332] BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and adjustment.

[0333] A BIMF score of 95 or below is considered herein to represent mild impairment in maternal functioning, a score of 80 or below is considered herein to represent impaired maternal functioning, and a score of 65 or below is considered herein to represent severe impairment in maternal functioning.

[0334] The inventors have determined that increased scores on the MADRS item "reduced sleep" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). Increased scores on the MADRS item "reduced sleep" impair self-care, psychological health and management.

[0335] 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.

[0336] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve improvements in sleep disturbances, particularly reduction or elimination of sleep loss.

[0337] The inventors also concluded that reducing or eliminating sleep loss by treating PPD patients resulted in a decrease in the total MADRS score and in an improvement in maternal functioning as reflected by an increase in the BIMF score.

[0338] The BIMF total score is improved by 10% or more, preferably by 20% or more.

[0339] Improvement in maternal function in patients suffering from PPD is reflected in at least an improvement in 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.

[0340] Improvement in maternal function in patients suffering from PPD (at least as reflected by improvement in 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 (at least as reflected by improvement in 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.

[0341] Persistent depressive disorder

[0342] Persistent depressive disorder, also called dysthymia, is a chronic form of depression. It is diagnosed if depression is present most of the time, most of the days, for at least 2 years. Any symptom-free period is less than 2 months.

[0343] To be 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.

[0344] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0345] In patients with persistent depressive disorder, altered functional connectivity within and / or between several brain regions associated with processing, regulation, emotional memory, cognitive processes associated with rumination, impaired concentration, and physiological arousal was observed. 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.

[0346] 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.

[0347] A 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.

[0348] The 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. The reduction or elimination of sleep disturbances 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.

[0349] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from persistent depressive disorder 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.

[0350] Improvements in sleep disturbances in patients suffering from persistent depressive 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.

[0351] Improvement of sleep disturbances in patients suffering from persistent depressive disorder (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 of sleep disturbances in patients suffering from persistent depressive disorder (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; 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, improvement in sleep disturbances in patients suffering from persistent depressive disorder (reflected by a decrease in CGI-S scores) 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.

[0353] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from persistent depressive disorder is reflected at least in an improvement in the score of 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.

[0354] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from persistent depressive disorder (at least 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 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.

[0355] In an embodiment, a reduction or elimination of sleep disturbances, in particular sleep loss, in patients suffering from persistent depressive disorder (reflected as 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.

[0356] 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) 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.

[0357] The reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder (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. The reduction or elimination of sleep disturbances in patients suffering from persistent depressive disorder (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0358] 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 lasts until at least 14 days, more preferably until at least 28 days.

[0359] As mentioned above, sleep disturbance is closely related to persistent depressive disorder. Therefore, improvement of sleep disturbance will also lead to improvement of persistent depressive disorder. In addition, since sleep disturbance will also affect other aspects of persistent depressive disorder, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of persistent depressive disorder.

[0360] Improvements in persistent depressive disorder in patients who also suffer from associated sleep disturbances are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in CGI-S scores.

[0361] Improvement in persistent depressive disorder in patients who also suffer from associated sleep disturbances (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 associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0362] In an embodiment, improvement in persistent depressive disorder in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0363] Sleep disturbance is also a common symptom of seasonal affective disorder.

[0364] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms typically starting in the fall and easing in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0365] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0366] People with seasonal affective disorder often feel extremely sleepy during the day, sleep longer than usual at night, have difficulty waking from long sleep periods, or feel the need to take naps repeatedly throughout the day, even though naps may not relieve the sleepiness. People with seasonal affective disorder also often have nightmares.

[0367] Sleep duration in relation 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 relating to sleep.

[0368] Resting-state activity involving sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared with healthy controls.

[0369] In patients with seasonal affective disorder, altered functional connectivity within and / or between several brain regions associated with processing, regulation, emotional memory, cognitive processes associated with rumination, impaired concentration, and physiological arousal was observed. 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.

[0370] 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.

[0371] 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.

[0372] The 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. The reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder 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.

[0373] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from seasonal affective disorder 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.

[0374] Improvements in sleep disturbances in patients suffering from seasonal affective disorder are observed as reflected in a decrease in CGI-S scores 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.

[0375] Improvement of sleep disturbance in patients suffering from seasonal affective disorder (reflected by 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 of sleep disturbance in patients suffering from seasonal affective disorder (reflected by a decrease in CGI-S score) 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.

[0376] In an embodiment, improvement in sleep disturbances in patients suffering from seasonal affective disorder (reflected by a decrease in CGI-S score) 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.

[0377] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from seasonal affective disorder is reflected at least in an improvement in the score of 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.

[0378] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from seasonal affective disorder (reflected as 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 seasonal affective disorder (reflected as 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.

[0379] In an embodiment, a reduction or elimination of sleep disturbances, in particular sleep loss, in patients suffering from seasonal affective disorder (reflected as 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.

[0380] 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.

[0381] The reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder (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. The reduction or elimination of sleep disturbances in patients suffering from seasonal affective disorder (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0382] 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 lasts until at least 14 days, more preferably until at least 28 days.

[0383] As mentioned above, sleep disturbance is closely related to seasonal affective disorder. Therefore, improvement of sleep disturbance will also lead to improvement of seasonal affective disorder. In addition, since sleep disturbance also affects other aspects of seasonal affective disorder, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of seasonal affective disorder.

[0384] Improvements in seasonal affective disorder in patients also suffering 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.

[0385] Improvement in seasonal affective disorder in patients who also suffer from an associated sleep disturbance (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 seasonal affective disorder in patients who also suffer from an associated sleep disturbance (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; 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, improvement in seasonal affective disorder in patients also suffering from an associated sleep disturbance (reflected by a decrease in CGI-S scores) 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] Bipolar disorder (BD) is a mental health condition characterized by dramatic mood swings, including low moods (major depressive episodes) and high moods (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.

[0388] Patients suffering from BD may suffer from a treatment-resistant form of the disorder.

[0389] If at least one manic episode occurs (with or without a depressive episode), BD is classified as bipolar disorder type I. If at least one hypomanic episode (but not a full manic episode) and one major depressive episode occur, BD is classified as bipolar disorder type II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

[0390] Patients with BD, whether diagnosed with bipolar II or bipolar I, are particularly susceptible to having a current major depressive episode.

[0391] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient 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.

[0392] 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.

[0393] Patients with BD (including bipolar I disorder and bipolar II disorder) are particularly prone to sleep disturbances, including changes in total sleep time (insomnia / hypersomnia) and circadian rhythm abnormalities.

[0394] A decreased need for sleep is often a sign of a manic episode.

[0395] 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.

[0396] During a manic episode, 69%-99% of patients experience sleep disturbances.

[0397] Sleep disturbances can lead to earlier relapse and decreased quality of life (reduced healthy behaviors and increased suicide risk).

[0398] Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. BDRS has been verified by trained assessors and can be used in clinical practice. According to clinical interviews, BDRS project assessments the severity of depression and / or mixed symptoms that patients show 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.

[0399] The problems addressed are: 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 motor drive; increased speech; agitation.

[0400] Each of these aspects was assessed and scored 0, 1, 2, or 3.

[0401] Sleep disturbance (sleep disorder) is assessed based on the change in the total amount of sleep within a 24-hour cycle and is not affected by external factors. The sleep disturbance can be manifested as insomnia (reduction in total sleep time) or hypersomnia (increase in total sleep time, including daytime sleep time).

[0402] Insomnia (reduction in total sleep time) was rated as 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).

[0403] Alternative measures of excessive sleepiness (increase in total sleep time, including daytime sleep time) 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).

[0404] Patients with bipolar disorder display characteristic abnormalities in the intrinsic organization and interconnectivity of resting-state networks. Resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network compared with healthy controls. In particular, altered functional connectivity within the default mode network has been observed in patients with sleep disturbances.

[0405] 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.

[0406] A 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.

[0407] The 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. The reduction or elimination of sleep disturbances in patients suffering from BD 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.

[0408] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from BD 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.

[0409] Improvements in sleep disturbances in patients suffering from BD, 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.

[0410] Improvement of sleep disturbance in patients suffering from BD (reflected by 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 of sleep disturbance in patients suffering from BD (reflected by a decrease in CGI-S score) 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.

[0411] 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.

[0412] Reduction or elimination of sleep disturbance 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.

[0413] The reduction or elimination of sleep disturbances in patients suffering from BD (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 (reflected by an improvement in the score of the BDRS item sleep disturbance) 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.

[0414] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from BD (reflected by 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.

[0415] Reduction or elimination of sleep disturbances, particularly sleep loss, in patients suffering from BD is reflected at least in an improvement in the score of 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.

[0416] The reduction or elimination of sleep disturbances (particularly sleep loss) in patients suffering from BD (reflected as 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 (reflected as 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.

[0417] In an embodiment, a reduction or elimination of sleep disturbances, in particular sleep loss, in patients suffering from BD (reflected as 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.

[0418] 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 below, 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.

[0419] The reduction or elimination of sleep disturbances in patients suffering from BD (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. The reduction or elimination of sleep disturbances in patients suffering from BD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0420] 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.

[0421] 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.

[0422] The reduction or elimination of sleep disturbances (particularly increased total sleep time) in patients suffering from BD (reflected by an improvement in the score of the BDRS item excessive 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 increased total sleep time) in patients suffering from BD (reflected by an improvement in the score of the BDRS item excessive 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.

[0423] In an embodiment, a reduction or elimination of sleep disturbances (particularly increased total sleep time) in patients suffering from BD (reflected as an improvement in the score of the BDRS item excessive sleep) 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.

[0424] As mentioned above, sleep disturbance is closely related to BD. Therefore, improvement of sleep disturbance will also lead to improvement of BD. In addition, since sleep disturbance also affects other aspects of BD, the inventors conclude that improvement of sleep disturbance will additionally contribute to the overall improvement of BD.

[0425] Improvements in BD 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.

[0426] Improvement in BD in patients who also suffer from associated sleep disturbances (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 BD in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0427] In an embodiment, improvement in BD in patients also suffering from associated sleep disturbances (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.

[0428] Anxiety disorders

[0429] Anxiety disorders are mental health conditions. Symptoms include feelings of nervousness, 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 preparation for an anticipated event or situation that is perceived as a threat.

[0430] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0431] People with anxiety disorders often experience sleep disturbances, especially insomnia. Excessive worry and fear can make it difficult to fall asleep and stay asleep throughout the night.

[0432] Insomnia can exacerbate anxiety, leading to a vicious cycle involving insomnia and anxiety.

[0433] The severity of anxiety disorders can be assessed by using the Hamilton Anxiety Rating Scale (HAM-A), which consists of 14 items, each defined by a series of symptoms, and measures mental anxiety (mental 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, dreams, nightmares, night terrors”. Each item is scored on a scale of 0 (absent) to 4 (severe), with a total score range of 0–56.

[0434] Sleep disturbances may also be assessed using, for example, the Pittsburgh Sleep Quality Index (PSQI) overall score.

[0435] Anxiety disorders are associated with altered functional connectivity of resting-state networks. Anxiety disorders manifest as abnormalities in the default mode network (DMN) that influences the sense of self, the salience network (SN) that controls emotion / anxiety, and the somatomotor network (SMN) that is responsible for body awareness. Relative to the DMN, the resting-state balance within and / or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

[0436] Altered functional connectivity in the affected networks has also been associated with disrupted sleep, and anxiety disorders have been linked to disrupted sleep.

[0437] Treatment of patients suffering from anxiety disorders (including treatment-resistant forms of said 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.

[0438] 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.

[0439] The 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. The reduction or elimination of sleep disturbances in patients suffering from anxiety disorders 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.

[0440] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from an anxiety disorder 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.

[0441] Improvements in sleep disturbances in patients suffering from anxiety disorders, 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.

[0442] Improvement of sleep disturbance in patients suffering from anxiety disorders (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 of sleep disturbance in patients suffering from anxiety disorders (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0443] In an embodiment, improvement in sleep disturbances in patients suffering from anxiety disorders (reflected by a decrease in CGI-S scores) 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.

[0444] 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.

[0445] The reduction or elimination of sleep disturbances in patients suffering from anxiety disorders (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. The reduction or elimination of sleep disturbances in patients suffering from anxiety disorders (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0446] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from anxiety disorders (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.

[0447] As mentioned above, patients with anxiety disorders will experience sleep disturbances. Therefore, improvement of sleep disturbances will also lead to improvement of anxiety disorders. In addition, since sleep disturbances can also affect other aspects of anxiety disorders, the inventors have concluded that improvement of sleep disturbances will additionally contribute to the overall improvement of anxiety disorders.

[0448] Improvements in anxiety disorders in patients who also suffer from associated sleep disturbances, 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.

[0449] Improvement in anxiety disorders in patients who also suffer from associated sleep disturbances (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 anxiety disorders in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] In an embodiment, improvements in anxiety disorders in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) are observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persist until at least 14 days, more preferably until at least 28 days.

[0451] Separation anxiety disorder is characterized by excessive anxiety about leaving home and / or being separated from people to whom the patient has a strong emotional attachment.

[0452] Separation situations can cause patients great distress, and they may have difficulty attending school or work because of the separation. People with separation anxiety disorder may also feel excessively anxious about unwelcome events that happen to important people in their lives, such as family members.

[0453] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0454] Separation anxiety disorder is associated with sleep disturbances. Sleep disturbances are even part of the diagnostic criteria for separation anxiety disorder. Sleep disturbances in patients with separation anxiety disorder include nightmares, difficulty falling asleep or staying asleep, early awakenings, and parasomnias.

[0455] 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. 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.

[0456] Sleep disturbance in separation anxiety disorder can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0457] Anxiety disorders are associated with altered functional connectivity of resting-state networks. Anxiety disorders manifest as abnormalities in the default mode network (DMN) that influences the sense of self, the salience network (SN) that controls emotion / anxiety, and the somatomotor network (SMN) that is responsible for body awareness. Relative to the DMN, the resting-state balance within and / or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

[0458] Altered functional connectivity in the affected network has also been associated with disrupted sleep, and separation anxiety disorder has been linked to disrupted sleep.

[0459] 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 of the separation anxiety disorder.

[0460] A 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.

[0461] The 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. The reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder 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.

[0462] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from separation anxiety disorder 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.

[0463] 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.

[0464] Improvement in sleep disturbances in patients suffering from separation anxiety disorder (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 (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0465] In an embodiment, improvement in sleep disturbances in patients suffering from separation anxiety disorder (reflected by a decrease in CGI-S scores) 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.

[0466] 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.

[0467] The reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder (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. The reduction or elimination of sleep disturbances in patients suffering from separation anxiety disorder (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0468] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from separation anxiety 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.

[0469] As mentioned above, sleep disturbance is a major discomfort symptom of patients suffering from separation anxiety disorder. Therefore, improvement of sleep disturbance will also lead to improvement of separation anxiety disorder. In addition, since sleep disturbance will also affect other aspects of separation anxiety disorder, the inventors conclude that improvement of sleep disturbance, especially alleviation or elimination of sleep loss, will additionally contribute to the overall improvement of separation anxiety disorder.

[0470] 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.

[0471] 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; 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.

[0472] In an embodiment, improvement in separation anxiety disorder in patients also suffering from an associated sleep disorder (reflected by a decrease in CGI-S scores) 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.

[0473] Agoraphobia is the fear of situations or places that may cause feelings of panic, entrapment, helplessness, or embarrassment.

[0474] People with agoraphobia may have difficulty leaving the house. The thought of leaving the house may cause considerable anxiety, even leading to avoidance. Fear of crowds, travel, elevators, movie theaters, shopping malls, etc. may cause significant challenges.

[0475] People with agoraphobia may also experience recurring panic attacks.

[0476] Patients suffering from agoraphobia may suffer from a treatment-resistant form of the disorder.

[0477] Agoraphobia is associated with sleep disturbances such as insomnia.

[0478] The severity of agoraphobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbance 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.

[0479] Sleep disturbance in agoraphobia can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0480] Functional magnetic resonance imaging of individuals with agoraphobia reveals alterations in functional connectivity within and / or between resting-state networks involved in anxiety.

[0481] 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 of the agoraphobia.

[0482] 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.

[0483] The 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. The reduction or elimination of sleep disturbances in patients suffering from agoraphobia 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.

[0484] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from agoraphobia 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.

[0485] Improvements in sleep disturbances in patients suffering from agoraphobia are observed as reflected in a decrease in CGI-S scores 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.

[0486] Improvement of sleep disturbances in patients suffering from agoraphobia (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 of sleep disturbances in patients suffering from agoraphobia (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] In an embodiment, improvement in sleep disturbances in patients suffering from agoraphobia (reflected by a decrease in CGI-S score) 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.

[0488] 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.

[0489] The reduction or elimination of sleep disturbances in patients suffering from agoraphobia (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. The reduction or elimination of sleep disturbances in patients suffering from agoraphobia (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0490] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from agoraphobia (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.

[0491] As mentioned above, sleep disturbance is a major symptom of patients suffering from agoraphobia. Therefore, improvement of sleep disturbance will also lead to improvement of agoraphobia. In addition, since sleep disturbance will also affect other aspects of agoraphobia, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of agoraphobia.

[0492] 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.

[0493] 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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] In an embodiment, improvement in agoraphobia in patients also suffering from an associated sleep disorder (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.

[0495] 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 may worry excessively about money, health, family, work, or other issues.

[0496] Generalized anxiety disorder is diagnosed when an individual experiences persistent worry about everyday challenges that is out of proportion to the perceived threat. People with GAD typically experience excessive fear that lasts for months to years.

[0497] GAD can interfere with social, occupational, or other important areas of functioning.

[0498] Patients suffering from GAD may suffer from a treatment-resistant form of the disorder.

[0499] A key feature of GAD is sleep disturbance, specifically difficulty falling asleep or staying asleep, or restless, 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 need to be present for a period of time to meet the diagnosis of GAD.

[0500] The severity of generalized 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. 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.

[0501] Sleep disturbance in GAD can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0502] Patients with GAD also show altered functional connectivity, particularly within the default mode network. Altered functional connectivity within the affected network has also been associated with sleep disturbances.

[0503] 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.

[0504] A 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.

[0505] The 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. The reduction or elimination of sleep disturbances in patients suffering from GAD 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.

[0506] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from GAD 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.

[0507] Improvements in sleep disturbances in patients suffering from GAD are observed as reflected in a decrease in CGI-S scores 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.

[0508] Improvement of sleep disturbance in patients suffering from GAD (reflected by 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 of sleep disturbance in patients suffering from GAD (reflected by a decrease in CGI-S score) 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.

[0509] In an embodiment, improvement in sleep disturbance in patients suffering from GAD (reflected by a decrease in CGI-S score) 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.

[0510] 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.

[0511] The reduction or elimination of sleep disturbances in patients suffering from GAD (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. The reduction or elimination of sleep disturbances in patients suffering from GAD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0512] 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.

[0513] As mentioned above, sleep disturbance is one of the most common major discomfort symptoms of patients with GAD. Therefore, improvement of sleep disturbance will also lead to improvement of GAD. In addition, since sleep disturbance also affects other aspects of GAD, the inventors conclude that improvement of sleep disturbance, particularly mitigation or elimination of sleep loss, will additionally contribute to the overall improvement of GAD.

[0514] Improvements in GAD in patients who also suffer from associated sleep disturbances, 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.

[0515] Improvement in GAD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated sleep disturbances 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 score) in patients who also suffer from associated sleep disturbances 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.

[0516] In an embodiment, improvements in GAD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) are observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persist until at least 14 days, more preferably until at least 28 days.

[0517] Social Anxiety Disorder (SAD) 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 may cause impairment in school, work, or interpersonal relationships.

[0518] Patients suffering from SAD may suffer from a treatment-resistant form of the disorder.

[0519] Sleep disturbances are very common in patients with social anxiety disorder due to the bidirectional relationship between sleep disturbances (primarily insomnia) and anxiety.

[0520] The severity of social 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. 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.

[0521] Sleep disturbance in social anxiety disorder can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0522] 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).

[0523] 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.

[0524] A 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.

[0525] The 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. The reduction or elimination of sleep disturbances in patients suffering from SAD 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.

[0526] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from SAD 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.

[0527] Improvements in sleep disturbances in patients suffering from SAD, 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.

[0528] Improvement of sleep disturbance in patients suffering from SAD (reflected by 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 of sleep disturbance in patients suffering from SAD (reflected by a decrease in CGI-S score) 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.

[0529] In an embodiment, improvement in sleep disturbance in patients suffering from SAD (reflected by a decrease in CGI-S score) 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.

[0530] 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 below, 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.

[0531] The reduction or elimination of sleep disturbances in patients suffering from SAD (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. The reduction or elimination of sleep disturbances in patients suffering from SAD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0532] 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.

[0533] 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 also affects other aspects of SAD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of SAD.

[0534] Improvements in SAD in patients who also suffer from associated sleep disturbances, 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.

[0535] Improvement in SAD (reflected by a decrease in CGI-S score) in patients who also suffer from associated sleep disturbances occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD (reflected by a decrease in CGI-S score) in patients who also suffer from associated sleep disturbances 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.

[0536] In an embodiment, improvement in SAD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0537] People with panic disorder experience spontaneous panic attacks, sudden onset of intense fear or discomfort that peaks within a few minutes.

[0538] 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.

[0539] In addition, the disorder can often be characterized by anxiety about future panic attacks. The patient may become extremely concerned about the possibility of another attack.

[0540] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0541] Sleep disturbances (particularly insomnia and hypersomnia) are very common in patients with panic disorder.

[0542] People with panic disorder may also experience nocturnal panic attacks, which are different from night terrors. Nocturnal panic attacks can occur without a trigger and often make it difficult to get back to sleep.

[0543] The severity of panic 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. The scale can further be used as an outcome measure of the treatment according to the invention by applying the scale before and after treatment.

[0544] Sleep disturbance in panic disorder can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0545] Patients with panic disorder show 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 characteristic of insomnia and hypersomnia.

[0546] 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.

[0547] 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.

[0548] The reduction or elimination of sleep disturbances in patients 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 patients suffering from panic disorder 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.

[0549] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from panic disorder 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.

[0550] Improvements in sleep disturbances in patients suffering from panic 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.

[0551] Improvement of sleep disturbance in patients suffering from panic disorder (reflected by 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 of sleep disturbance in patients suffering from panic disorder (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0552] In an embodiment, improvement in sleep disturbances in patients suffering from panic disorder (reflected by a decrease in CGI-S score) 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.

[0553] Reduction or elimination of sleep disturbances in patients suffering from panic 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.

[0554] The reduction or elimination of sleep disturbances in patients suffering from panic disorder (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. The reduction or elimination of sleep disturbances in patients suffering from panic disorder (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0555] 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.

[0556] As mentioned above, sleep disturbance is very common in patients with panic disorder. Therefore, improvement of sleep disturbance will also lead to improvement of panic disorder. In addition, since sleep disturbance also affects other aspects of panic disorder, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of insomnia and / or excessive sleep, will additionally contribute to the overall improvement of panic disorder.

[0557] Improvements in panic disorder in patients also suffering 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.

[0558] Improvement in panic 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 panic 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; 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.

[0559] In an embodiment, improvement in panic disorder in patients also suffering from an associated sleep disorder (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.

[0560] A phobia is an anxiety disorder characterized by a persistent and excessive fear of an object or situation. People with phobias experience extreme anxiety when anticipating or coming into contact with the phobic stimulus. There are phobias of animals (spiders, snakes, dogs), natural environments (tornadoes, heights, water, fire), blood injections (needles, medical procedures), situations (flying in airplanes, enclosed spaces), and others (those that don't fit into the previous categories).

[0561] Phobias usually cause a rapid onset of fear and are usually present for more than six months. The person will go to great lengths to avoid the feared stimulus. The fear and avoidance may cause significant distress and / or impairment in occupational, academic, or social functioning.

[0562] Patients suffering from phobias may suffer from a treatment-resistant form of the disorder.

[0563] There is evidence that patients with phobias have an increased likelihood of experiencing sleep disturbances.

[0564] The severity of phobia can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbance is an integral part of the scale. The scale can further be used as an outcome measure of the treatment according to the present invention by applying the scale before and after treatment.

[0565] Sleep disturbance in phobias can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0566] Phobias are also reflected in altered functional connectivity of resting-state networks, such as those involving the amygdala and insula, and the salience network, which also plays a role in insomnia.

[0567] 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 improvements in the phobias.

[0568] A 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.

[0569] The reduction or elimination of sleep disturbances in patients suffering from phobias 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 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.

[0570] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a phobia 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.

[0571] Improvements in sleep disturbances in patients suffering from phobias are observed as reflected by a decrease in CGI-S scores 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.

[0572] Improvement of sleep disturbance in patients suffering from phobias (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 of sleep disturbance in patients suffering from phobias (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0573] In an embodiment, improvement in sleep disturbances in patients suffering from phobias (reflected by a decrease in CGI-S scores) 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.

[0574] Reduction or elimination of sleep disturbances in patients suffering from phobias 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.

[0575] The reduction or elimination of sleep disturbances in patients suffering from phobias (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. The reduction or elimination of sleep disturbances in patients suffering from phobias (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0576] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from phobias (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.

[0577] As mentioned above, patients with phobias are more likely to experience sleep disturbances. Therefore, improvement of sleep disturbances will also lead to improvement of phobias. In addition, since sleep disturbances can also affect other aspects of phobias, the inventors conclude that improvement of sleep disturbances, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of phobias.

[0578] Improvements in phobias in patients who also suffer from associated sleep disturbances, 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.

[0579] Improvement in phobias (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 phobias (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; 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, improvement in phobias in patients also suffering from an associated sleep disorder (reflected by a decrease in CGI-S scores) 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.

[0581] 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 or medication use.

[0582] The disorder causes significant distress and / or impairment in social, occupational, or other important areas of functioning.

[0583] During or shortly after taking a substance or medication, an individual with a substance / medication-induced anxiety disorder may feel nervous and worried, experience symptoms of negative thinking, may have trouble 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, trouble breathing, difficulty swallowing, or chest pain.

[0584] Patients suffering from substance / medication induced anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0585] Substance / medication-induced anxiety disorders are also associated with sleep disturbances. Patients may have trouble falling asleep or may wake up frequently during the night.

[0586] The severity of substance / medication-induced anxiety disorders can be assessed using the Hamilton Anxiety Rating Scale (HAM-A), wherein the assessment of sleep disturbance 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.

[0587] Sleep disturbance in substance / medication-induced anxiety disorders can also be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0588] Functional magnetic resonance imaging of individuals with substance / medication-induced anxiety disorders reveals alterations in functional connectivity within and / or between resting-state networks involved in anxiety.

[0589] Treatment of patients suffering from substance / drug induced anxiety disorders (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 substance / drug induced anxiety disorder.

[0590] 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.

[0591] The 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. The reduction or elimination of sleep disturbances in patients suffering from substance / medication induced anxiety disorders 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.

[0592] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from a substance / medication induced anxiety disorder 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.

[0593] Improvements in sleep disturbances in patients suffering from substance / medication induced anxiety disorders, 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.

[0594] Improvement of sleep disturbances in patients suffering from substance / medication induced anxiety disorders (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 of sleep disturbances in patients suffering from substance / medication induced anxiety disorders (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0595] 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 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.

[0596] 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) 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.

[0597] The reduction or elimination of sleep disturbances in patients suffering from substance / medication induced anxiety disorders (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. The reduction or elimination of sleep disturbances in patients suffering from substance / medication induced anxiety disorders (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0598] 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, 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.

[0599] As mentioned above, sleep disturbance is a major symptom of discomfort in patients with substance / drug-induced anxiety disorders. Therefore, improvement of sleep disturbance will also lead to improvement of substance / drug-induced anxiety disorders. In addition, since sleep disturbance will also affect other aspects of substance / drug-induced anxiety disorders, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of substance / drug-induced anxiety disorders.

[0600] Improvements in substance / medication-induced anxiety disorders in patients who also suffer from associated sleep disturbances are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in CGI-S scores.

[0601] Improvement in substance / medication-induced anxiety disorders in patients who also suffer from associated sleep disturbances (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 substance / medication-induced anxiety disorders in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] In an embodiment, improvements in substance / medication-induced anxiety disorders in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) are observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persist until at least 14 days, more preferably until at least 28 days.

[0603] Somatic symptom disorder

[0604] Somatic symptom disorder is a mental disorder that is 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 daily life. Feelings and behaviors associated with the disorder are excessive or disproportionate.

[0605] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorder, the impairment is significant, and when it persists, the disorder may lead to disability.

[0606] Patients with somatic symptom disorder may report disrupted sleep (ie, insomnia, patient dissatisfaction with the quality, timing, and amount of sleep) that causes daytime distress and impairment.

[0607] Sleep disturbances have the potential to create a veritable vicious cycle between physical symptoms and sleep disturbance.

[0608] For example, insomnia has been associated with the presence of somatic symptoms, and the severity of insomnia has been associated with the severity of somatic symptoms. However, this effect is not limited to insomnia, as changes in the sleep-wake cycle have themselves been associated with the occurrence of somatic symptoms.

[0609] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptoms - Adults measure. This measure includes 15 somatic symptoms. Respondents are asked to rate the severity of 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 bothering"), "1" ("a little bothering") to "2" ("very bothering"). 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 represent low, moderate, and high somatic symptom severity, respectively.

[0610] Additionally, sleep disturbances in individuals with somatic symptom disorder can be assessed using the Pittsburgh Sleep Quality Index.

[0611] Brain 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 sensory discrimination processing of somatic symptoms, which is affected by affective processing.

[0612] 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.

[0613] 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.

[0614] The 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. The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder 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.

[0615] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from somatic symptom disorder 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.

[0616] Improvements in sleep disturbances in patients suffering from somatic symptom 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.

[0617] Improvement of sleep disturbance in patients suffering from somatic symptom disorder (reflected by 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 of sleep disturbance in patients suffering from somatic symptom disorder (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] In an embodiment, improvement in sleep disturbance in patients suffering from somatic symptom disorder (reflected by a decrease in CGI-S score) 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.

[0619] 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) 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.

[0620] The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder (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. The reduction or elimination of sleep disturbances in patients suffering from somatic symptom disorder (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0621] 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, 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.

[0622] As mentioned above, sleep disturbance is common in patients with somatic symptom disorder. Therefore, improvement of sleep disturbance will also lead to improvement of somatic symptom disorder. In addition, since sleep disturbance can also affect other aspects of somatic symptom disorder, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of somatic symptom disorder.

[0623] Improvements in somatic symptom disorder in patients who also suffer from associated sleep disturbances, 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.

[0624] 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; 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.

[0625] 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 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.

[0626] Obsessive-compulsive disorder and related disorders

[0627] 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 have both obsessions and compulsions.

[0628] Patients suffering from OCD may suffer from a treatment-resistant form of the disorder.

[0629] Sleep disturbance is a common feature of patients with OCD. There is a correlation between the presence of sleep disturbance and the severity of OCD.

[0630] Sleep disturbances have been associated with treatment resistance in OCD, so addressing symptoms will improve treatment outcomes.

[0631] Neuroimaging studies using functional magnetic resonance imaging on patients with OCD have shown altered functional connectivity within and / or between the frontoparietal, salience, and default mode networks. Altered functional connectivity of the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

[0632] 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.

[0633] A 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.

[0634] The 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. The reduction or elimination of sleep disturbances in patients suffering from OCD 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.

[0635] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from OCD 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.

[0636] Improvements in sleep disturbances in patients suffering from OCD, 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.

[0637] Improvement of sleep disturbance in patients suffering from OCD (reflected by 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 of sleep disturbance in patients suffering from OCD (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0638] In an embodiment, improvement in sleep disturbances in patients suffering from OCD (reflected by a decrease in CGI-S score) 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.

[0639] 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.

[0640] The reduction or elimination of sleep disturbances in patients suffering from OCD (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. The reduction or elimination of sleep disturbances in patients suffering from OCD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0641] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from OCD (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.

[0642] As mentioned above, sleep disturbance is common in patients with OCD. Therefore, improvement of sleep disturbance will also lead to improvement of OCD. In addition, since sleep disturbance also affects other aspects of OCD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of OCD.

[0643] Improvements in OCD in patients who also suffer from associated sleep disturbances, as reflected by reductions in CGI-S scores, are observed on day 1, e.g., about 24 hours after; 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.

[0644] Improvement in OCD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated sleep disturbances 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 by a decrease in CGI-S score) in patients who also suffer from associated sleep disturbances 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.

[0645] In an embodiment, improvements in OCD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) are observed on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persist until at least 14 days, more preferably until at least 28 days.

[0646] People with body dysmorphic disorder (BDD) falsely perceive imperfections in their appearance that disrupt their ability to live daily lives and are accompanied by disturbing thoughts, ritualistic behaviors, and emotional distress.

[0647] Patients suffering from BDD may suffer from a treatment-resistant form of the disorder.

[0648] 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 more impairment in daily functioning.

[0649] Functional magnetic resonance imaging of patients with BDD revealed alterations within and / or between certain brain regions located within the default mode network, dorsal attention network, and salience network. Altered functional connectivity of the affected networks, particularly the default mode network, has also been associated with sleep disturbances.

[0650] 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.

[0651] A 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.

[0652] The 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. The reduction or elimination of sleep disturbances in patients suffering from BDD 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.

[0653] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from BDD 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.

[0654] Improvements in sleep disturbances in patients suffering from BDD, 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.

[0655] Improvement of sleep disturbance in patients suffering from BDD (reflected by 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 of sleep disturbance in patients suffering from BDD (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; 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 sleep disturbances in patients suffering from BDD (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.

[0657] Reduction or elimination of sleep disturbances in patients 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.

[0658] The reduction or elimination of sleep disturbances in patients suffering from BDD (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. The reduction or elimination of sleep disturbances in patients suffering from BDD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0659] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from BDD (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.

[0660] As mentioned above, sleep disturbance is common in patients with BDD. Therefore, improvement of sleep disturbance will also lead to improvement of BDD. In addition, since sleep disturbance can also affect other aspects of BDD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of BDD.

[0661] Improvements in BDD in patients who also suffer from associated sleep disturbances, 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.

[0662] Improvement in BDD (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 BDD (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0663] In an embodiment, improvement in BDD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0664] Post-traumatic stress disorder (PTSD)

[0665] Post-traumatic stress disorder (PTSD) is a mental health condition that can develop based on a terrifying event that the patient has experienced or witnessed. Symptoms can include flashbacks, nightmares, and severe anxiety and uncontrollable thoughts about the event.

[0666] Patients suffering from PTSD may suffer from a treatment-resistant form of the disorder.

[0667] 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).

[0668] 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.

[0669] Sleep disturbances in PTSD can be assessed by self-administered questionnaires, such as the PTSD Symptom Inventory or the Trauma Screening Questionnaire (TSQ).

[0670] The self-report version of the PTSD Symptom Scale is a 17-item self-report questionnaire that assesses symptoms of PTSD. Sleep disturbances were assessed in the form of bad dreams or nightmares or difficulty falling or staying asleep. Respondents were asked to indicate how often they had 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). Scores of 13 or higher indicate the likelihood of PTSD.

[0671] In the trauma screening questionnaire, two of the 10 items analyze sleep (bad dreams, or trouble falling asleep, or trouble staying asleep) and require a yes or no answer. Six or more positive answers indicate a risk for PTSD.

[0672] 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.

[0673] 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 improvements in PTSD.

[0674] A 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.

[0675] 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 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.

[0676] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from PTSD 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.

[0677] 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.

[0678] Improvement of sleep disturbances in patients suffering from PTSD (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 of sleep disturbances in patients suffering from PTSD (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0679] In an embodiment, improvement in sleep disturbances in patients suffering from PTSD (reflected by a decrease in CGI-S scores) 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.

[0680] 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.

[0681] The reduction or elimination of sleep disturbances in patients suffering from PTSD (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. The reduction or elimination of sleep disturbances in patients suffering from PTSD (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0682] In an embodiment, a reduction or elimination of sleep disturbances in a patient suffering from PTSD (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.

[0683] As mentioned above, sleep disturbance is an important aspect of PTSD. Therefore, improvement of sleep disturbance will also lead to improvement of PTSD. In addition, since sleep disturbance also affects other aspects of PTSD, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of PTSD.

[0684] Improvements in PTSD in patients who also suffer from associated sleep disturbances, as reflected by reductions in CGI-S scores, are observed at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] Improvement in PTSD in patients who also suffer from associated sleep disturbances (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 PTSD in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0686] In an embodiment, improvements in PTSD in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) are observed 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persist until at least 14 days, more preferably until at least 28 days.

[0687] Pain disorders

[0688] Sleep disturbances occur in patients with pain and are associated with chronic pain.

[0689] 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.

[0690] The prevalence of insomnia (defined as dissatisfaction with sleep quantity or quality, difficulty falling asleep, staying asleep, or awakening too early) in chronic pain populations is nearly twice as high as that in the general population, estimated at 24%-32%.

[0691] When sleep disturbances are defined using polysomnography, actinography, or self-report measures, the prevalence estimates rise to 40%-80% in chronic pain patients.

[0692] The relationship between sleep disturbance and chronic pain is thought to be bidirectional, however insomnia may later develop into a separate disorder requiring direct targeted treatment. Other disorders associated with sleep disturbance, such as depression and anxiety, are highly prevalent in the chronic pain population.

[0693] The relevance of sleep disturbance to chronic pain is also reflected in, for example, the Brief Pain Inventory-Short Form (BPI-sf), a 9-item self-administered questionnaire that assesses the severity of a patient's pain and the impact of such pain on the patient's daily functioning. One item of the BPI-sf is sleep. The questionnaire asks about the interference of pain with sleep during the past 24 hours. Therefore, sleep disturbance is a relevant aspect of chronic pain.

[0694] Chronic pain patients display brain alterations regarding both function and structure. These changes are associated with the persistence of pain, long after the initial noxious input has ceased. Resting-state functional magnetic resonance imaging reveals alterations in distinct regions within and / or between the default mode network, somatomotor / sensorimotor networks, and salience networks.

[0695] 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 improvements in chronic pain.

[0696] 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.

[0697] The 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. The reduction or elimination of sleep disturbances in patients suffering from chronic pain 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.

[0698] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from chronic pain 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.

[0699] 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.

[0700] Improvement in sleep disturbances in patients suffering from chronic pain (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 (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0701] In an embodiment, improvement in sleep disturbances in patients suffering from chronic pain (reflected by a decrease in CGI-S score) 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.

[0702] 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.

[0703] The reduction or elimination of sleep disturbances in patients suffering from chronic pain (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. The reduction or elimination of sleep disturbances in patients suffering from chronic pain (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0704] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from chronic pain (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.

[0705] As mentioned above, sleep disturbance is an important disease aspect for patients suffering from chronic pain. Therefore, improvement of sleep disturbance will also lead to improvement of chronic pain. In addition, since sleep disturbance also affects other aspects of chronic pain, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of chronic pain.

[0706] Improvements in chronic pain in patients who also suffer from associated sleep disturbances are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in CGI-S scores.

[0707] Improvement in chronic pain in patients who also suffer from associated sleep disturbances (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 chronic pain in patients who also suffer from associated sleep disturbances (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0708] In an embodiment, improvement in chronic pain in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0709] Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain throughout the body or in multiple sites, along with fatigue, sleep disturbances, memory and mood problems. Sufferers may also experience muscle and joint stiffness, tenderness, numbness or tingling in the arms and legs, difficulty concentrating, unclear thinking and memory loss (sometimes called "fibro fog"), increased sensitivity to light, noise, smells and temperature, or digestive problems, such as bloating or constipation.

[0710] Studies have shown that people with fibromyalgia have a heightened sensitivity to pain, so they feel pain when others don’t.

[0711] Sleep problems and fatigue are common symptoms of fibromyalgia. Insomnia, non-restorative sleep, and fatigue are often used as markers for the diagnosis of fibromyalgia. People with fibromyalgia may also suffer from restless legs syndrome.

[0712] Sleep disturbance in fibromyalgia can be assessed using the Pittsburgh Sleep Quality Index (PSQI).

[0713] There is a bidirectional relationship between fibromyalgia and sleep disturbance. Pain symptoms prevent patients from getting enough rest, while lack of sleep can lower pain thresholds and increase perceptions of pain and tenderness.

[0714] The interaction of pain, fatigue, and poor sleep quality often affects patients' ability to function at home or work.

[0715] Previous treatments for fibromyalgia were symptomatic.

[0716] Brain imaging studies and other research have found evidence that people with fibromyalgia have 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.

[0717] Resting-state functional magnetic resonance imaging in patients with fibromyalgia revealed altered functional connectivity within and / or between the DMN and executive attention networks, and between the DMN and the insular cortex, a brain region known to process evoked pain.

[0718] 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 improvements in fibromyalgia.

[0719] 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.

[0720] The 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. The reduction or elimination of sleep disturbances in patients suffering from fibromyalgia 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.

[0721] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from fibromyalgia 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.

[0722] 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.

[0723] Improvement in sleep disturbances in patients suffering from fibromyalgia (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 (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0724] In an embodiment, improvement in sleep disturbances in patients suffering from fibromyalgia (reflected by a decrease in CGI-S score) 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.

[0725] Reduction or elimination of sleep disturbances in patients suffering from fibromyalgia 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.

[0726] The reduction or elimination of sleep disturbances in patients suffering from fibromyalgia (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. The reduction or elimination of sleep disturbances in patients suffering from fibromyalgia (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0727] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from fibromyalgia (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.

[0728] As mentioned above, sleep disturbance is one of the most common major discomfort symptoms of patients suffering from fibromyalgia. Therefore, improvement of sleep disturbance will also lead to improvement of fibromyalgia. In addition, since sleep disturbance also affects other aspects of fibromyalgia, the inventors conclude that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of fibromyalgia.

[0729] Improvements in fibromyalgia 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.

[0730] Improvement in fibromyalgia (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in fibromyalgia (as reflected by a decrease in CGI-S score) in patients who also suffer from an associated 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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0731] In an embodiment, improvement in fibromyalgia in patients also suffering from associated sleep disturbances (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.

[0732] A migraine is a type of headache that causes severe throbbing pain or a pulsating sensation, usually on one side of the head. Migraines are often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. Migraine attacks can last from a few hours to a few days, and the pain can be so severe that it interferes with daily activities.

[0733] In some patients, a symptom called an aura occurs before or at the same time as the headache. This symptom can include visual disturbances, such as flashes of light or blind spots, or other disturbances, such as tingling on one side of the face or in an arm or leg, and difficulty speaking.

[0734] The most common sleep disturbance in patients with migraine is insomnia. This includes difficulty falling asleep or staying asleep, early morning awakenings, and non-restorative sleep. Insomnia impairs daytime functioning, leading to fatigue, poor concentration, and loss of motivation.

[0735] The presence of sleep disturbance was associated with more frequent and severe migraines.

[0736] The Pittsburgh Sleep Quality Index (PSQI) is a common self-report sleep quality questionnaire that assesses sleep quality over the past month and has been used in many studies to assess poor sleep quality in patients with migraine.

[0737] Headache disorders were associated with atypical functional connectivity in regions involved in pain processing and within and / or between multiple core resting-state networks, including the salience network and the default mode network.

[0738] In patients with migraine, resting-state network analyses revealed differences from healthy controls. Studies during migraine attacks revealed significant abnormalities in networks involved in mediating cognitive, attentional, somatosensory, and affective components of pain.

[0739] Treatment of patients suffering from migraine 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 migraine.

[0740] Reduction or elimination of sleep disturbances in patients suffering from migraine 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.

[0741] The reduction or elimination of sleep disturbances in patients suffering from migraine 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 migraine 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.

[0742] In an embodiment, reduction or elimination of sleep disturbances in a patient suffering from migraine 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.

[0743] Improvements in sleep disturbances in patients suffering from migraine, 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.

[0744] Improvement of sleep disturbance in patients suffering from migraine (reflected by 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 of sleep disturbance in patients suffering from migraine (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; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0745] In an embodiment, improvement in sleep disturbance in patients suffering from migraine (reflected by a decrease in CGI-S score) 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.

[0746] Reduction or elimination of sleep disturbances in patients suffering from migraine 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.

[0747] The reduction or elimination of sleep disturbances in patients suffering from migraine (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. The reduction or elimination of sleep disturbances in patients suffering from migraine (reflected by an improvement in the PSQI overall score, in particular a decrease in the overall score to 5 or below) 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.

[0748] As mentioned above, sleep disturbance is one of the most common major discomfort symptoms of patients suffering from migraine. Therefore, improvement of sleep disturbance will also lead to improvement of migraine. In addition, since sleep disturbance can also affect other aspects of migraine, the inventors have concluded that improvement of sleep disturbance, especially reduction or elimination of sleep loss, will additionally contribute to the overall improvement of migraine.

[0749] In an embodiment, a reduction or elimination of sleep disturbances in patients suffering from migraine (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.

[0750] Improvements in migraine 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.

[0751] Improvement in migraine headaches (as reflected by a decrease in CGI-S scores) in patients who also suffer from associated sleep disturbances occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in migraine headaches (as reflected by a decrease in CGI-S scores) in patients who also suffer from associated sleep disturbances 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.

[0752] In an embodiment, improvement in migraine in patients also suffering from associated sleep disturbances (reflected by a decrease in CGI-S scores) 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.

[0753] Mental and behavioral disorders due to psychoactive substance use

[0754] Sleep disturbances occur in patients with certain psychiatric and behavioral disorders caused by the use of psychoactive substances.

[0755] Substance use disorder (SUD) is a mental disorder that affects a person's behavior, causing a person to lose control of their use of substances (such as legal or illegal drugs, alcohol, or medications). Symptoms can range from moderate to severe, and addiction is the most severe form of SUD.

[0756] Resting-state functional connectivity (rsFC) was found to be altered not only in patients with sleep disorders but also in patients with substance use disorders. Specifically, cognitive control deficits were associated with altered connectivity within and / or between resting-state networks such as the default mode network, salience network, central executive network, limbic network, and reward network.

[0757] Substance / medication-related sleep disorders are characterized by alterations in sleep patterns severe enough to require independent clinical attention and judged to be primarily caused by the pharmacological effects of the substance (i.e., drugs of abuse, medications, toxin exposure).

[0758] Sleep disturbances may be the result of substance intoxication and / or withdrawal, such as alcohol, caffeine, marijuana, opioids, sedatives (hypnotics or anxiolytics), tobacco, stimulants (such as cocaine), or other substances.

[0759] Certain medications, such as adrenergic agonists / antagonists, dopamine agonists / antagonists, cholinergic agonists / antagonists, serotonergic agonists / antagonists, antihistamines, or corticosteroids can also cause sleep disturbances.

[0760] Depending on the substance involved, one of four types of sleep disturbance is reported. Insomnia and daytime sleepiness are the most common, and parasomnias are less common. When more than one type of sleep disturbance-related symptoms are present and no one symptom is dominant, it is considered a mixed type.

[0761] Because the withdrawal state from some substances can be prolonged, sleep disturbances may develop as early as four weeks after cessation of substance use and may have features atypical of other sleep disorders (eg, age of onset or atypical course).

[0762] The serious impact of sleep disturbance in substance use disorders is reflected in the development of specialized sleep questionnaires, such as the Substance Use Sleep Scale (SUSS). The SUSS questionnaire contains 23 questions and 2 domains: "physical and mental sleep problems" and "substance-related sleep problems". The score range is 0-23, with lower scores indicating better sleep and higher scores indicating worse sleep.

[0763] Treatment of patients suffering from substance use disorder and associated sleep disturbances with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the sleep disturbances and resu...

Claims

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

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use 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 as claimed in 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 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 100, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 100, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

104. 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.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 101 or 104, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 105, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 101 or 104, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 107, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 104 to 108, 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.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 100 to 109, 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.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 110, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 111, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

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