5-Methoxy-N,N-dimethyltryptamine for the treatment of psychomotor retardation

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat patients suffering from psychomotor retardation.

Description

[Technical field]

[0001] The present invention is directed to improved methods for the treatment of psychomotor retardation in patients suffering from psychiatric or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorders (SUD), psychotic disorders, e.g., schizophrenia, dementia, e.g., Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's disease dementia, Parkinson's disease, chronic fatigue syndrome.

[0002] Psychomotor retardation can also occur in patients suffering from sleep disorders, such as insomnia.

[0003] The treatment involves administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof. [Background technology]

[0004] Psychomotor retardation is characterized by reduced energy and activity, and reduced motivation. Psychomotor retardation involves a slowing of thinking and a decrease in physical movement in an individual. Psychomotor disorders can cause a noticeable slowing of physical and emotional responses.

[0005] Thus, there is a need for improved methods of treating psychomotor retardation, particularly psychomotor retardation associated with psychiatric or nervous system disorders. Summary of the Invention

[0006] Specifically, it is an object of the present invention to provide improved therapies that are more effective than the aforementioned therapies (i.e., a) a higher percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a more rapid onset of clinical response, and / or d) a more sustained clinical response).

[0007] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens thereof that have a better safety profile and / or are better tolerated than the aforementioned therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens thereof that are more convenient than the aforementioned therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens thereof that are associated with higher patient compliance rates (including higher treatment initiation rates) than the aforementioned therapies. A still further object of the present invention is to identify specific disease aspects and specific subgroups of disease aspects that would benefit from such improved psychoactive therapies.

[0008] The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharma- ceutically acceptable salt thereof, for use in the treatment of a patient suffering from psychomotor retardation.

[0009] The present invention provides improved methods for the treatment of psychomotor retardation, in particular in patients suffering from psychiatric or nervous system disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, such as substance use disorders (SUD), psychotic disorders, such as schizophrenia, dementia, such as Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's disease dementia, Parkinson's disease, chronic fatigue syndrome.

[0010] The present invention also provides improved methods for the treatment of psychomotor retardation in patients suffering from sleep disorders, such as insomnia.

[0011] The present invention also provides dosage ranges and regimens useful for treating psychomotor retardation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition When used in the context of the present invention, unless otherwise noted, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are specifically acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated from the weight of the free base, assuming that an equimolar amount is used.

[0013] As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed by a licensed professional in accordance with recognized medical practice as suffering from psychomotor retardation, or as having a psychiatric or nervous system disorder associated with psychomotor retardation, in which case the assessment of psychomotor retardation may or may not be part of the diagnosis.

[0014] The diagnosis of mental or nervous system disorders can be according to, for example, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will be evident from the discussion of the specific conditions below, the criteria may be modified or supplemented to better define patients or groups of patients who will particularly benefit from treatment according to the invention. In any case, the diagnosis is by a physician or psychologist. It is not sufficient that the human subject himself considers himself to be suffering from the disorder.

[0015] As used in the context of the present invention, unless otherwise noted, the terms "treat" and "treatment" shall include the management and care of a patient to combat a disease, condition, or disorder, and includes the administration of compounds and the practice of methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0016] "Treatment of psychomotor retardation" is intended to include the management and care of a patient to combat psychomotor retardation, and includes the administration of compounds and practices of the methods according to the invention to alleviate the signs and / or symptoms of psychomotor retardation or to eliminate psychomotor retardation.

[0017] The psychomotor retardation may be associated with a sleep disorder, eg, insomnia, a psychiatric or nervous system disorder, or another medical condition.

[0018] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not improved sufficiently after at least two appropriate treatment courses.Specifically, the patient has not improved sufficiently after at least two appropriate treatment courses, where at least one of the two courses is drug therapy, for example, the patient has not improved sufficiently after at least two appropriate drug therapy courses.The at least two previous treatment courses are specifically implemented during the current episode of the disease, for example, during the current depressive episode if the patient suffers from a disorder characterized by depressive episodes.

[0019] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" is intended to mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician or other clinician, which biological or clinical response in humans includes alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0020] "Clinical response" includes, but is not limited to, improvements on rating scales that assess: (i) psychomotor retardation or an aspect of psychomotor retardation, and / or (ii) psychiatric or nervous system disorders or an aspect of such disorders, and / or (iii) sleep.

[0021] Symptom severity, as well as change in severity, can be assessed by the Clinical Global Impression (CGI) scale, a measure of symptom severity, treatment response, and treatment efficacy.

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

[0023] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in this patient?" This is rated on a 7-point scale: 1 = normal (no illness at all), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, 7 = patients with very severe illness.

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

[0025] The clinical response may be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means a reduction in the CGI-S score of at least one grade. Preferably, a reduction in the CGI-S score of at least two grades and / or a score of 0. Particularly preferred is a reduction in the CGI-S score of at least three grades and / or a score of 0.

[0026] Alternatively, the success of the treatment can be evaluated using the CGI-Improvement (CGI-I), the format of which is similarly brief. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, only one question is rated on a 7-point scale: "Compared to the patient's condition at the time of entry into the project (before starting medication), this patient's condition has improved 1=very much since starting treatment, 2=significantly improved, 3=minimally improved, 4=unchanged from baseline (at the start of treatment), 5=minimally worsened, 6=significantly worsened, 7=very much worsened since starting treatment."

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

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

[0029] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") is intended to mean the introduction of a possible amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered by nasal inhalation, by buccal administration or by sublingual administration.

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

[0031] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharma- ceutically acceptable gas, such as air) and extremely small suspended solids and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When a percentage of "degradation products" is described in the context of the present invention, it refers to the amount of 5-MeO-DMT decomposition products present in the sample divided by the amount of 5-MeO-DMT present in the sample plus the amount of 5-MeO-DMT decomposition products present in the sample, multiplied by 100%, i.e., (the sum of the amount of all 5-MeO-DMT decomposition products present in the sample) / ((the amount of 5-MeO-DMT present in the sample)+(the sum of the amount of all 5-MeO-DMT decomposition products present in the sample))×100%. As used herein, the term "impurities" refers to undesirable compounds that contaminate a 5-MeO-DMT (or a pharma-ceutically acceptable salt thereof) sample. The impurities may be contained in the starting material prior to formation of the aerosol, or the impurities may be decomposition products.

[0032] The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) / (the amount of 5-MeO-DMT present + the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0033] The term "mass median aerodynamic diameter" (MMAD) is the calculated diameter where 50% of the particles present in the aerosol are larger and 50% are smaller than this diameter. The term "aerosol particle mass concentration" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle generation rate" refers to the mass of aerosolized 5-MeO-DMT per unit time of aerosolization.

[0034] Psychomotor retardation An important aspect observed in patients suffering from psychomotor retardation is the decrease in energy and activity, as well as the decrease in motivation.

[0035] Psychomotor retardation involves a slowing of thinking and a decrease in physical movements in an individual. Psychomotor disorders can cause a noticeable slowing of physical and emotional responses.

[0036] Psychomotor retardation may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0037] Mental or nervous system disorders causing or associated with psychomotor retardation include disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorders (SUD), psychotic disorders, e.g., schizophrenia, dementia, e.g., Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's disease dementia, Parkinson's disease, chronic fatigue syndrome, and the like.

[0038] Psychomotor retardation can also occur in patients suffering from sleep disorders, such as insomnia.

[0039] Measurement of psychomotor retardation Psychomotor retardation can be assessed by measuring various aspects, which may include, for example, various types of drawing tasks and tests, such as the Trail Making Test (TMT), the Digit Symbol Substitution Test (DSST), or the Gibson Spiral Maze Test (GSM), as well as other tests known in the art.

[0040] For example, in the Trail Making Test (TMT), subjects must connect 25 circles containing numbers (TMT A) or combinations of numbers and letters (TMT B) in ascending order. The task requirements are similar for TMT-B, except that subjects must alternate between numbers and letters (1, A, 2, B, 3, C, etc.). Thus, the test assesses processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the time needed to complete the task.

[0041] Another test requiring graphomotor skills is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not influenced by cognitive ability: subjects completing the GSM must correctly traverse a spiral maze from start to finish without touching the boundaries.

[0042] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of a digit-symbol pair followed by a digit list. Under each digit, the subject must write down the corresponding symbol as quickly as possible. The score consists of the number of symbols correctly reported in 90 seconds. A further example of a motor test is the finger tapping test.

[0043] Thus, certain tests combine measurements of both the motor and cognitive aspects of psychomotor retardation, while still other tests assess only the motor aspect.

[0044] Speech analysis may be a further indicator of psychomotor retardation.

[0045] The main scales available for assessment and measurement include severity of psychomotor retardation, the Salpêtrière Retardation Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

[0046] The Salpêtrière Retardation Rating Scale (SRRS), developed by Widlocher, assesses cognitive and motor aspects with 15 items. The first three measure movement, specifically stride quality, as well as slowness of limb, trunk, head, and neck movements. The next three items focus on speech, including speech flow, tone, and length of response. Two items are designed to objectively measure cognitive function. These questions are dialogue-based and measure the patient's ability to engage and expand on a topic. Further items are subjective, assessing rumination, fatigue, level of interest, time perception, memory, and concentration. The last item of the scale concerns an overall assessment of the patient's psychomotor retardation. These items are scaled from 0 (no symptoms) to 4 (severe) based on the severity of the presenting symptoms, with a total score ranging from 0 to 60.

[0047] The Motor Agitation and Retardation Scale (MARS) assesses only motor aspects. It was designed to assess psychomotor impairments in depressive disorders. Psychomotor impairments are classified into five major physical categories including eyes, face, voice, limbs, and trunk, totaling 19 items of the scale. Items in the eye category include direction of gaze, blink amount, gaze, and eye movement. Items related to the face category include facial expression and expressiveness. The voice category has items including voice volume, intelligibility, tone, and voice onset time. The limb category includes hands, feet, and leg movements, striding, slowness of movement, and hand tension. Items in the trunk category include posture, immobility, and axial movement. The severity of each item ranges from 1 to 4, with 4 being the most severe. Of the 19 items, 9 items are related to motor agitation and 10 items assess motor retardation. Delays include abnormal gait, immobility of trunk / proximal limbs, poor posture, slowness of movement (i.e., Limb and Trunk category), lack of expressiveness, downcast eyes (i.e., Eye and Face category), and reduced vocal volume, slurred speech, delayed speech initiation, monotonous speech (i.e., Voice category). The MARS scale provides a rapid clinical assessment of motor signs.

[0048] Scales for assessing psychiatric and nervous system disorders A number of scales have been suggested for assessing the severity of psychiatric or nervous system disorders. Such scales are based on tests that can be self-administered or administered by a clinician.

[0049] Scales that may be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0050] Treatment outcome is assessed using one or more indexes or measures at one or more time points following completion of a course of therapy.

[0051] The assessment may be performed after the acute hallucinatory experience has subsided. An appropriate time point for early assessment is generally about 2-3 hours after the last administration. Early assessments may generally be performed, for example, about 2 hours or about 3 hours after the last administration.

[0052] However, evaluation of the effect on sleep disorders can be performed as early as the day after treatment (ie, day 1) so that treated patients have had the opportunity to sleep at least overnight.

[0053] Thus, evaluation at day 1 or evaluation on day 1 means evaluation on the day after dosing. Evaluation will occur no earlier than 12 hours after the last dose, and in any event no earlier than one night after the last dose and no later than 36 hours after the last dose. Evaluation may occur after about 24 hours.

[0054] Assessment on day 7 or assessment at day 7 refers to the assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment times measured in days.

[0055] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response at an early time point (e.g., 2 hours) after drug administration based on an evaluation item developed for a longer recall period (e.g., for MADRS, usually 7 days), a reasonable modification of such evaluation item (e.g., changing MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration) can be applied. The same applies to other scales applied herein, unless recall period is specifically indicated.

[0056] At early time points the considerations outlined apply, on the one hand because the influence of the patient's condition before treatment on any scores recorded after treatment to assess the clinical response should be kept as low as possible, and on the other hand because sleep items cannot be assessed 2 hours after administration of the drug.

[0057] At later time points (e.g., day 1 or later), all items on the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0058] Resting-state networks and psychomotor retardation Brain processes can be studied by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0059] Functional brain images are acquired over a period of several minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anti-correlated fluctuations.

[0060] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that show coordinated activity even in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent signal fluctuation patterns are called resting-state networks (RSNs).

[0061] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the activation patterns seen in resting-state networks and task-fMRI experiments.

[0062] Thus, resting-state fMRI can be used to assess the intrinsic functional organization of the brain: resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0063] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks have been found to be impaired in various disease states, including certain forms of psychomotor retardation, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0064] For example, functional connectivity abnormalities have been reported from the somatosensory-motor network (SMN) to the visual network (VN), dorsal attention network (DAN), and default mode network that correlate with both psychomotor retardation and psychomotor agitation in depressive disorders.

[0065] In many cases, resting state networks involved in psychomotor retardation are affected by psychiatric or nervous system disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, such as substance use disorders (SUD), psychotic disorders, such as schizophrenia, dementia, such as Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's disease dementia, Parkinson's disease, chronic fatigue syndrome.

[0066] The resting state networks involved in psychomotor retardation are also affected by sleep disorders, such as insomnia, and in fact, psychomotor retardation and sleep disorders are correlated.

[0067] Treatment of psychomotor retardation and mental or nervous system disorders According to the present invention, it is possible to treat psychomotor retardation in patients suffering from psychiatric or nervous system disorders, and further, it is possible to treat psychomotor retardation occurring in patients suffering from sleep disorders, such as insomnia.

[0068] In patients suffering from psychomotor retardation in association with another condition detailed above, treatment of psychomotor retardation according to the invention results in an improvement in the condition with which the psychomotor retardation is associated.

[0069] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0070] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption results in the resetting of ill-connected pathological connections as the networks reconnect. New healthy functional connections are established with lasting effects.

[0071] Thus, in accordance with the present invention, affecting these resting state networks by the therapies described herein will result in improvement of psychomotor retardation, and, if the treated patient suffers from a psychiatric or nervous system disorder, will also result in improvement of that disorder, and, if the treated patient suffers from a sleep disorder, e.g., insomnia, will also result in improvement of the sleep disorder, e.g., insomnia.

[0072] To further support the clinical application of 5-MeO-DMT in patients suffering from psychomotor retardation, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and noted specific improvements in psychomotor retardation that are typically also observed in patients with other disorders.

[0073] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD, see also the Examples section below.) Although TRD is a specific condition, the inventors have determined that certain clinical observations made in this study are relevant to the design of treatments for other conditions associated with psychomotor retardation, as discussed in detail below.

[0074] In clinical trials, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. Of interest in the context of the present invention are those that received a single dose of 12 mg and those that received an intraday individualized dosing schedule (IDR), which allows for multiple ascending doses (6 mg, 12 mg and 18 mg) over the course of a day driven by the intensity of the patient-reported hallucinatory experience.

[0075] Data collected included treated patients' assessments on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). While the focus of the study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on items across the various scales and noted that specific subscore items, such as those related to psychomotor retardation, may be related to other conditions based on similarly altered functional connectivity within and / or between somatomotor / sensorimotor networks, visual networks, dorsal attention networks, and default mode networks.

[0076] Multiple patients within the recruited cohort exhibited significant improvement, supporting the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients with these conditions.

[0077] More specifically, an aspect that can be treated by administration of 5-MeO-DMT is psychomotor retardation. 5-MeO-DMT can be administered to a patient to reduce or eliminate psychomotor retardation in the patient.

[0078] The MADRS scale item that is particularly relevant to psychomotor retardation is "fatigue," which describes difficulty in initiating movements or slowness in initiating and carrying out daily activities.

[0079] A score of 0 means that there is almost no difficulty in starting anything and no slowness. If the patient has difficulty starting activities, a score of 2 is assigned. A score of 4 means that simple daily activities are difficult to start and require effort to perform. In the case of complete fatigue, a score of 6 is assigned and the patient is unable to do anything without help.

[0080] The aggregate MADRS item "fatigue" score across all eight patients in the study arm receiving the individualized dosing regimen was 27 at baseline.

[0081] After 2 hours, the score was reduced to 10, which corresponds to an improvement of 17 points or 63%. On the first day after treatment, the score was reduced to 5, which corresponds to an improvement of 22 points or 81%. On the seventh day after treatment, the score was reduced to 3, which corresponds to an improvement of 24 points or 89%.

[0082] In the 12 mg group, the aggregate score for the MADRS item "fatigue" across all four patients was 16 at baseline. After 2 hours, the score had decreased to 10, corresponding to a 6-point or 38% improvement. On the first post-treatment day, the score had decreased to 0, corresponding to a 16-point or 100% improvement. On the seventh post-treatment day, the score had decreased to 3, corresponding to a 13-point or 81% improvement.

[0083] Thus, the score for "fatigue", a scale item particularly relevant to psychomotor retardation, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat psychomotor retardation in patients, particularly those who also suffer from a psychiatric or nervous system disorder, or a sleep disorder, such as insomnia.

[0084] As a result, in accordance with the present invention, treating a patient suffering from psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation.

[0085] Active Agent The above discussion indicates that psychomotor retardation presents a significant disease burden in its own right and merits appropriate treatment.

[0086] The inventors reasoned that carefully selected hallucinogens might lead to improved treatment of important aspects of psychomotor retardation, possibly leading to an overall improvement of the condition.

[0087] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also called serotonin receptors (seven families are described, 5-HT1 to 5-HT7, with several subtypes). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "hallucinogens" to highlight their predominant ability to induce qualitatively altered states of consciousness, such as euphoria, trance states, time and space transcendence, spiritual experiences, dissolution of self-boundaries, or even near-death experiences, while other effects, such as sedation, narcosis, or hyperstimulation, are minimal.

[0088] Chemically, serotonergic hallucinogens are either phenylalkylamines or indolamines, and the indolamine class is divided into two subsets, the ergolines and tryptamines, the latter being derived from tryptamine.

[0089] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and trace amine-associated receptors.

[0090] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using the DMT-containing shamanic brew ayahuasca) in certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, which may preclude their clinical use.

[0091] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who suffered a manic attack after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that disappeared, but were followed about 3 weeks later by a typical manic episode of psychotic magnitude. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ingestion of ayahuasca, a DMT-containing brew, in a man with bipolar disorder.

[0092] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0093] The inventors have considered that in order to avoid induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound administered must be appropriately selected and, preferably, administered in a specific dosing regimen.

[0094] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogenic agent for use in therapy. 5-MeO-DMT has a distinct pharmacological profile that differs from other hallucinogenic compounds.

[0095] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both the 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0096] The inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after uptake of psilocybin), DMT, and 5-MeO-DMT are further detailed in the Examples section below. i The inhibition constants (K values) of psilocin, DMT, and 5-MeO-DMT are 48, 38, and 1.80 nM, respectively, at 5-HT1A receptors located in the hippocampus of postmortem human brains. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, whereas psilocin and DMT exhibit intermediate affinity. The inhibition constants (K values) of psilocin, DMT, and 5-MeO-DMT are 48, 38, and 1.80 nM, respectively, at 5-HT1A receptors located in the hippocampus of postmortem human brains. iThe 5-HT2A receptors located in the frontal cortex of postmortem human brains have a potency of 37, 117, and 122 nM, respectively. Thus, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0097] Compared with other psychoactive compounds mentioned above, 5-MeO-DMT presents enhanced affinity to 5-HT1A receptors, where 5-MeO-DMT acts as a strong agonist.In the case of psilocin and DMT, the contribution to 5-HT2A binding is increased compared with 5-MeO-DMT, and the latter presents the largest affinity difference for 5-HT1A over 5-HT2A of these three compounds.Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared with 5-HT2A binding for the other two compounds.

[0098] It has been reported that 5-HT1A receptor agonism reduces impulsivity and aggression, while 5-HT2A receptor agonism may increase these same traits in the short term. Furthermore, the dopamine system has been implicated in mania, with increased dopaminergic activity being associated with mania. LSD, psilocybin, and DMT all display increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0099] Compared to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT can be administered to patients, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder, psychotic disorders, such as schizophrenia, or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or nervous system disorders treated according to the present invention do not experience treatment-emerged mania or hypomania.

[0100] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use seem to indicate that large amounts of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD) were used.

[0101] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0102] Furthermore, antidepressants have been reported to induce isolated hypomanic events in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0103] 5-MeO-DMT can induce peak experiences (i.e. experiences characterized by a shift in emotional perspective described as "loss of self"), often leading to an overwhelming feeling of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g. 5-30 minutes after inhalation versus several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile that can be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0104] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have demonstrated that 5-MeO-DMT is a 5-HT7 receptor agonist and has a high affinity for the receptor. 3 H]LSD, and serotonin were used to estimate nonspecific binding, and K i was determined to be 2.3 nM.

[0105] Thus, in addition to the 5-HT1A and 5-HT2A receptors mentioned above, 5-MeO-DMT also interacts with the 5-HT7 receptor, for which it acts as an agonist and shows high (nanomolar) binding affinity.

[0106] 5-HT7 receptors have a role in neurogenesis, synaptogenesis and dendritic spine formation, among others, they are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0107] 5-HT7 receptors are specifically expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and cerebellum.

[0108] 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, specifically those involving sleep disorders. Resting-state functional connectivity analysis in patients suffering from sleep disorders reveals altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0109] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the receptor's function in regulating the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on the receptor.

[0110] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as one mediator of the pharmacological effects of 5-MeO-DMT with its "resetting" of functional network connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

[0111] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as well as to the 5-HT1A receptor, as two mediators of the effects exerted by 5-MeO-DMT, including the functional connectivity "resetting" of the network and neuroplasticity effects, allows to achieve beneficial effects even in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, negative thinking, sleep disorders, or social / emotional withdrawal. This is supported by the clinical results demonstrated in the studies referred to herein.

[0112] Another characteristic of 5-MeO-DMT is its short half-life.

[0113] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0114] The present inventors have investigated the pharmacokinetic properties of 5-MeO-DMT and found that inhaled 5-MeO-DMT was rapidly absorbed and distributed, with maximum concentrations and pharmacological effects observed during and shortly after administration.

[0115] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations drop very rapidly. Already 10 minutes after administration, concentrations are below 10% of Cmax, after 2 hours they are below 1% of Cmax, and after 3 hours 5-MeO-DMT is no longer detectable in plasma. This is true over the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed upon repeated dosing within a 1-4 hour time frame. Titrating the dose as disclosed herein does not result in accumulation and therefore does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after dosing.

[0116] The properties of 5-MeO-DMT make this compound particularly suitable for the treatment of psychomotor retardation, particularly in patients suffering from psychiatric or neurological disorders.

[0117] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0118] According to the present invention, isotopic variants of 5-MeO-DMT and pharma- ceutically acceptable salts thereof may also be used. When referring to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0119] Such variants are specifically deuterated forms of 5-MeO-DMT and pharma- ceutically acceptable salts of such forms.

[0120] A deuterated form of 5-MeO-DMT is one that has a higher deuterium content than expected based on the natural abundance of this isotope.

[0121] Deuterated forms of 5-MeO-DMT are specifically forms in which deuterium has been introduced at one or more defined hydrogen positions.

[0122] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0123] Further examples include forms of 5-MeO-DMT in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Still further examples include forms of 5-MeO-DMT in which hydrogen atoms of the indole ring system are replaced with one or more deuterium atoms. It should be noted that combinations of the above substitution patterns are also contemplated.

[0124] Methods for preparing these compounds are known in the art.

[0125] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharma- ceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT and salts of non-deuterated 5-MeO-DMT may also be used.

[0126] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in molar amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0127] According to the present invention, prodrugs of 5-MeO-DMT and pharma- ceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, this may be replaced by a 5-MeO-DMT prodrug or a salt thereof.

[0128] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be cleaved off after administration.

[0129] An example of a suitable organic moiety is -C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 And each R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0130] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 , and R 4 is defined as above.

[0131] Prodrugs, especially those of the above structure, can also be used in the form of pharma- ceutically acceptable salts.

[0132] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, specifically ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0133] Methods for preparing the prodrugs described herein are known in the art.

[0134] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hours or less, particularly 0.5 hours or less.

[0135] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0136] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is administration by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in one breath.

[0137] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration preparation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0138] Buccal or sublingual administration can also be by a pharma- ceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in a formulation as is commonly known in the art (e.g., tablets, films, sprays, creams).

[0139] The administration is specifically by inhalation of an aerosol. Such an aerosol contains (a) a pharma- ceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, specifically about 2 mg / l to about 9 mg / l). The pharma- ceutical acceptable gas is preferably air.

[0140] The aerosol particles preferably contain less than 1 wt% impurities, specifically less than 0.5 wt% impurities, and more preferably contain less than 0.5 wt% 5-MeO-DMT decomposition products, specifically less than 0.2 wt% 5-MeO-DMT decomposition products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0141] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0142] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0143] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0144] The aerosol may be formed by a) exposing a thin layer of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to generate aerosol particles. The thin layer may have a thickness of less than about 10 μm, specifically less than about 7.5 μm. The thin layer may have a thickness in the range of about 0.1 μm to about 10 μm, specifically in the range of about 0.3 μm to about 7.5 μm.

[0145] A thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via air passing over the thin layer. Alternatively, a thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via the solid support.

[0146] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. Specifically, the air passing over the thin layer may have a temperature of about 210° C. and may pass over the thin layer at a flow rate of about 12 liters / minute for about 15 seconds.

[0147] The aerosol particles can be contained in a volume of about 3 liters or less, specifically, a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0148] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharma- ceutically acceptable salt thereof is provided in the form of an aerosol. Such an aerosol has a suitable aerosol particle mass concentration so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0149] The aerosol useful in the present invention can be formed using thermal energy.When thermal energy is used to form aerosol of a compound, particularly when the aerosol is to be used to deliver the compound to a patient systemically via the lungs, it is very difficult to predict the conditions suitable for safe, efficient and predictable aerosolization.Relevant variables in this context include: a) the dose of the compound, b) the morphological state (e.g., crystalline form, or thin layer form) in which the compound is made available for aerosolization, c) the amount of thermal energy that the compound is exposed to (defined by exposure temperature and exposure duration), and d) the amount of air that is introduced to generate the aerosol (defined by flow rate and duration of air flow).

[0150] The compositions and methods described herein are for the safe, efficient and predictable systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized, preferably nearly completely or completely, to a defined extent, that the aerosol has physical properties desirable for systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., within one deep breath), and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0151] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

[0152] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT configured on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0153] The generation of aerosol particles characterized by an aerodynamic mass median diameter of less than 3 microns, containing less than 1% wt of impurities and less than 0.5% wt of 5-MeO-DMT degradation product drug in the aerosol volume, and capable of being delivered to a patient via a single inhalation, is achieved by defining a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the exposure temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by the air flow rate and duration of air flow).

[0154] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, in which case the air is heated. The temperature of the heated air passing over the thin layer may range from about 180° C. to about 260° C. The temperature of the air passing over the thin layer may specifically be about 210° C.

[0155] Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180° C. to about 420° C.

[0156] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, being at least 99%, preferably at least 99.5% pure.

[0157] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0158] The solid support on which 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided may have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders less than 1.0 mm in diameter, boxes less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a large surface area to volume ratio (e.g., greater than 100 per meter) and a large surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0159] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface area to volume ratio of about 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (about 400 per meter).

[0160] A number of different materials are used to construct the solid support. Such material types include, but are not limited to, metals, inorganic materials, carbon-containing materials, and polymers. Examples of material types are: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0161] When aluminum is used as the solid support, aluminum foil is a preferred material. Examples of silica, alumina and silicon based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m 2 1 / g alumina (Aldrich, St. Louis, Mo.) and silicon wafers such as those used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0162] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, specifically less than about 7.5 μm. The thin layer may have a thickness in the range of about 0.1 μm to about 10 μm, specifically in the range of 0.3 μm to 7.5 μm.

[0163] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of about 6 liters per minute to about 40 liters per minute, preferably about 8 liters per minute to about 16 liters per minute, and the duration of the air flow is selected so that the total volume of the aerosol does not exceed about 3 liters, and the total volume of the aerosol is preferably about 1 liter to 3 liters (such as 2 liters to 3 liters). For example, at an air flow rate of about 6 liters per minute, the duration of the air flow should be less than about 30 seconds. A specific useful air flow rate and duration of the air flow are about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific useful air flow rate and duration of the air flow are about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific useful air flow rate and duration of the air flow are about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0164] The aerosol generation rate is greater than 0.1 mg / sec.

[0165] The aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, specifically, about 2 mg / l to about 9 mg / l).

[0166] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0167] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT decomposition products, preferably less than 0.2% wt of 5-MeO-DMT decomposition products.

[0168] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT configured on a solid support as a thin layer less than 5 microns thick to a temperature of 210° C. for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt of 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0169] Those skilled in the art who are aware of the aerosol characteristics and aerosolization conditions defined in the present invention can identify suitable vaporization devices or systems that lead to the required aerosol characteristics. Examples of such suitable vaporization devices or systems include, for example, the Volcano Medic vaporization system (Storz & Bickel (Germany), disclosed in, for example, EP0 933 093 B1 and EP1 884 254 B1, and Registered Community Design 003387299-0001) with an associated dosing capsule equipped with a drip pad, and the Staccato device (Alexza Pharmaceuticals (Mountain View, USA), disclosed in, for example, US7,458,374 B2, US9,370,629 B2, and US9,687,487 B2). The generated aerosol is collected in a balloon from which it can be inhaled by the patient.

[0170] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (dosing schemes).

[0171] The present invention is based in part on the inventors' conclusion that the occurrence of a peak hallucinatory experience during the acute phase following administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, either in a causal relationship or at least as a surrogate behavioral marker for the underlying unknown therapeutic mechanism, drives its therapeutic benefit in patients suffering from psychomotor retardation, specifically one or more of the above-defined aspects.

[0172] Thus, achieving a peak experience more rapidly, in a greater percentage of patients, and with greater reproducibility within an individual patient compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0173] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., no attenuation or disappearance of the hallucinogenic effect after re-administration) as the basis for enabling a dosing regimen with frequent re-administration (e.g., more than once a day or daily) designed to increase the incidence of peak experiences and thereby increase the therapeutic effect. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time point), induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur at higher doses, thereby affecting the experience at higher doses in a positive way. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance at the patient population level.

[0174] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate of peak experiences and modulate the reproducibility of peak experiences, as well as to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the delayed onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration) that may last for several days.

[0175] Patients as defined herein suffering from psychomotor retardation are treated by administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0176] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other treatment for psychomotor retardation.

[0177] The dosage of 5-MeO-DMT administered to a patient as defined herein suffering from psychomotor retardation is in the range of about 1 mg to about 25 mg, or any amount within that range, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. The patient may also be treated with an equimolar dose of a pharma- ceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. It should be noted that, when a range is given herein, such as "about 1 mg to about 25 mg," the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0178] In a preferred embodiment, the improved method for treating a patient as defined herein suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT comprises that a clinical response occurs by about 2 hours after administration of 5-MeO-DMT.

[0179] In a preferred embodiment, the improved method for treating a patient as defined herein suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT comprises a sustained clinical response, including a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT and occurs 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.

[0180] In a preferred embodiment, the improved method for treating a patient as defined herein suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT comprises administration of more than a single dose of 5-MeO-DMT.

[0181] In a preferred embodiment, the greater than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2-7 administrations, the interval between each administration within each treatment block being greater than or equal to about 1 hour and less than or equal to about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being greater than or equal to about 6 days.

[0182] In an even more preferred embodiment, the greater than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0183] In a most preferred embodiment, the greater than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1-3 doses, with the interval between each dose within each treatment block being about 1-4 hours, preferably 1-2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0184] In certain 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 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0185] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0186] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0187] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increment is 6 mg, the dosage of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage of the third administration will be 18 mg.

[0188] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration and to a dosage selected from about 14 mg to about 20 mg for the third administration, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects. Specific amounts useful for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0189] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 20 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a hallucinogenic high experience at a dose of 18 mg, and therefore the highest dosage in the first treatment block was 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0190] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, then increased to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dosage selected from about 14 mg to about 20 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts useful for the first, second, and third administrations within the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0191] It is understood that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0192] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0193] The occurrence of a "hallucinatory peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0194] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0195] In accordance with the present invention, the occurrence of a "hallucinatory peak experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control was it? 3. How profound (i.e., meaningful) was the experience?

[0196] Treatment of psychomotor retardation and sleep disorders Sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether it is idiopathic or occurs in association with a medical condition, such as a psychiatric or nervous system disorder.Sleep disorder affects a person's ability to function properly while awake, and is associated with patterns of high negative affect and low positive affect.

[0197] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Non-REM sleep and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Earlier in the night, non-REM sleep is deeper, taking up a disproportionate amount of time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with more of each cycle being allocated to REM sleep.

[0198] Normal healthy sleep consists of the various stages outlined above that proceed in a consecutive and strictly regulated sequence throughout the night.

[0199] Any disruption of this strict regulation leads to sleep disorders.

[0200] Common forms of sleep disorders include problems falling asleep and staying asleep (insomnia), excessive sleepiness (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), functional disorders related to sleep, sleep stages, or partial awakening (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders). In a broad sense, fatigue can also be considered a sleep disorder.

[0201] Insomnia is a sleep disorder in which people have difficulty falling asleep or staying asleep. People with insomnia have at least one daytime problem, such as difficulty falling asleep, waking up frequently during the night and having trouble falling asleep again, waking up too early in the morning, not getting restorative sleep, and / or fatigue, sleepiness, mood disorders, difficulty concentrating, accidents at work or while driving, due to poor quality sleep.

[0202] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in people with hypersomnia. This is a difficulty in the transition from sleep to wakefulness. Individuals experiencing sleep drunkenness report awakenings that are accompanied by confusion, disorientation, slowness, and repeated returns to sleep.

[0203] Circadian rhythm disorders are characterized by chronic or recurrent sleep disorders resulting from alterations in an individual's internal circadian rhythm or from misalignment between the individual's circadian rhythm and the individual's desired or necessary work or social schedule. This desynchronization can be temporary or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep duration is usually shortened and interrupted, performance during desirable wakefulness is impaired, and temporary opportunities to return to a normal sleep schedule are unsuccessful.

[0204] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) that people experience before sleep, during sleep, or during periods of arousal between sleep and wakefulness. There is considerable variation in terms of characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0205] Sleep-related breathing disorders are characterized by breathing abnormalities and difficulty in breathing during sleep. Breathing is a complex process that depends heavily on the coordinated action of respiratory muscles and the brain. These sleep disorders can seriously affect sleep and the balance of oxygen and carbon dioxide in the blood, and therefore manifest as chronic snoring, sleep apnea, sleep-related hypoventilation, and / or hypoxemia. In some of these disorders, breathing is also abnormal during wakefulness. Reduced airflow causes intermittent hypoxia, with microarousals or awakenings, leading to sleep fragmentation and excessive daytime sleepiness. Inflammation and endothelial dysfunction may follow, leading to reduced vascular elasticity, increased clotting, and potentially predisposing individuals to atherosclerosis, which, together with reduced oxygen supply, can cause heart and brain damage.

[0206] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0207] Fatigue refers to a state of fatigue that is not relieved by rest or sleep. It is a feeling of exhaustion, lethargy, or reduced energy that is usually experienced as a weakening or depletion of physical or mental resources and is characterized by a reduced capacity to work and a decreased efficiency in responding to stimuli. Fatigue is normal after periods of mental or physical exertion, but can sometimes occur in the absence of such exertion as a symptom of a health condition.

[0208] Not getting adequate quantity and quality of sleep can lead to personality changes and may even exacerbate existing psychiatric disorders or even trigger the onset of new psychiatric disorders.

[0209] Elderly people are at particular risk for sleep disorders, such as insomnia and circadian rhythm disorders. Severe and persistent sleep disorders in elderly patients can lead to neuropsychiatric symptoms, such as psychomotor retardation. Poor sleep can also negatively impact quality of life by contributing to the development of obesity, diabetes, and heart disease.

[0210] Treatment for sleep disorders varies depending on the type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatments may also include medication or psychotherapy.

[0211] Available treatments are not successful in all patients, may be associated with side effects, and / or may require treatment for extended periods of time to achieve the relevant therapeutic benefit.

[0212] In patients suffering from a sleep disorder associated with a psychiatric or nervous system disorder, known treatments for the psychiatric or nervous system disorder do not necessarily improve the sleep disorder.

[0213] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement of the associated sleep disorders. Although most antidepressants have been shown to affect sleep mechanics, some classes of antidepressants improve sleep, whereas others may cause sleep disorders (Hutka et al. Association of Sleep Architecture and Physiology with Depressive Disorder and Antidepressants Treatment. Int J Mol Sci. 2021 Jan 29; 22(3): 1333., Abstract).

[0214] To assess sleep, parameters such as sleep duration, sleep architecture, sleep latency, and frequency and duration of nighttime awakenings can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-report scales (questionnaires).

[0215] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic. A variety of functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, posture and body movements, snoring, and heart rate.

[0216] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep during multiple test naps. A mean sleep latency of about 10 minutes is considered normal, with less than 8 minutes indicating a sleep disorder. Concomitant analysis of brain activity can aid in further diagnosis of sleep disorders.

[0217] The sleep assessment questionnaire records ratings of components of sleep quality such as perception of sleep depth, difficulty waking up, and feeling restful after sleep, in addition to other factors that may affect sleep quality such as comorbid conditions and medication use.

[0218] Assessment of qualitative aspects of the sleep experience is important because sleep complaints may often persist despite normality of quantitative measures of sleep.

[0219] Questionnaires may not only facilitate a rapid and accurate assessment of complex clinical problems but also help to track the progress of patients. Self-reported sleep questionnaires completed by patients are therefore an important pillar for the assessment of sleep disorders in clinical practice.

[0220] Various sleep quality indices are known. The following indices include examples of questionnaires for assessing general sleep, as well as examples of specific questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias, respectively. However, the present invention is not limited to the use of any particular index or questionnaire.

[0221] Sleep quality can generally be assessed using, for example, the Sleep Quality Scale (SQS) and the Sleep 50 Questionnaire.

[0222] The Sleep Quality Scale (SQS) is a comprehensive assessment tool to obtain a general and efficient scale suitable for assessing sleep quality in various patient and research populations. Individual questions about daytime symptoms such as attention, concentration, or memory difficulties (item 15 "Lack of sleep makes it hard to think", item 19 "Lack of sleep makes me make mistakes at work", item 21 "Lack of sleep makes me forget things", item 22 "Lack of sleep makes it hard to concentrate at work"), recovery after sleep, problems initiating and maintaining sleep, difficulty waking up, and satisfaction with sleep can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more acute sleep problems.

[0223] The Sleep-50 questionnaire consists of 50 items designed to screen for various types of sleep disorders in the general population. The scale consists of nine subscales reflecting some of the most common disorders and complaints related to sleep, as well as factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a scale ranging from 1 ("not at all") to 4 ("completely true") and asked to indicate the extent to which the statement matches their experiences over the past month or another appropriate recall time frame.

[0224] This questionnaire requires that, in order to diagnose a sleep disorder, not only certain subscales (e.g., insomnia) must exceed certain cutoff points, but also the impact subscale (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46. (See Table 4 for optimal cutoffs and scoring procedure).

[0225] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0226] A common questionnaire to assess sleep disorders is the Pittsburgh Sleep Quality Index. Other instruments include the Insomnia Severity Index and the Espie sleep disturbance questionnaire.

[0227] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbance. The PSQI is a self-rated questionnaire that includes 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another suitable recall period.

[0228] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleep medications, and (7) daytime functioning disorders.

[0229] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbance. Detailed scoring procedures for the Pittsburgh Sleep Quality Index can be found in the appendix to Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0230] The scores on the seven components are then summed to produce a single overall score ranging from 0 to 21 points, with "0" indicating no difficulties and "21" indicating severe difficulties in all areas. The cutoff value for the overall score is 5, which distinguishes between those with and without sleep problems. A total score of >5 indicates that the patient has severe difficulties in at least two areas or moderate difficulties in more than three areas.

[0231] When the PSQI is used to assess treatment outcome, success of treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0232] The Insomnia Severity Index (ISI) is a five-item questionnaire on subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning (item 3 “To what extent do you think your sleep problems interfere with daily functioning (e.g., daytime fatigue, ability to function at work / daily chores, concentration, memory, mood, etc.)”), how noticeable the respondent perceives their insomnia compared to others, and the overall level of distress caused by the sleep problems. Individual responses can be scored from 0 (= none) to 4 (= very), with higher total scores corresponding to more severe insomnia. A total score of 0–7 indicates “not clinically significant insomnia”, 8–14 means “subthreshold insomnia”, 15–21 is “clinical insomnia (moderate severity)”, and 22–28 means “clinical insomnia (severe)” (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012, Bastien et al. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med.2001 Jul;2(4):297-307).

[0233] The typical recall time frame for the ISI is two weeks, although other suitable recall time frames may be used herein.

[0234] Successful treatment is indicated by (i) a reduction in score, for example, by more than 7 points, particularly more than 8 points, and preferably (ii) a reduction below the cutoff for clinically significant insomnia.

[0235] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. With ratings of restlessness / agitation, mental hyperactivity, consequences of insomnia, and poor sleep preparation, the SDQ specifically relates to beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate how often certain statements about insomnia describe their experience, with 1 meaning "never" and 5 meaning "very often." Higher scores indicate more impaired beliefs about the causes and correlates of insomnia (A. Shahid et al., loc.cit.; Espie et al. Insomniacs' attributions. psychometric properties of the Dysfunctional Beliefs and Attitudes about Sleep Scale and the Sleep Disturbance Questionnaire. J Psychosom Res. 2000 Feb;48(2):141-8).

[0236] Successful treatment is indicated by a reduction in score.

[0237] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0238] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents how likely they are to fall asleep under eight different circumstances, representing moments of relative inactivity such as an afternoon nap or sitting in a stationary car stuck in traffic. Using a scale of 0 to 3 (0 meaning "never doze off" and 3 meaning "likely to doze off"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies daytime sleepiness at a subclinical level (A.Shahid et al.,loc.cit. Johns et al.,A new method for measuring daytime sleepiness:the Epworth sleepiness scale. Sleep,1991 Dec;14(6):540-5).

[0239] Successful treatment is indicated by (i) a reduction in score, preferably (ii) to 10 or less.

[0240] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a particular moment. The scale consists of only one item and asks the respondent to select one of seven statements that best describes their current perceived level of sleepiness. A scale ranging from 1 (= active and full of energy, alert, completely awake) to 7 (= almost daydreaming, falling asleep quickly, losing effort to stay awake) is used to assess the level of sleepiness (A. Shahid et al., loc.cit.; Hoddes et al. The development and use of the Stanford sleepiness scale (SSS). Psychophysiology, 1972, 9, 150).

[0241] Successful treatment is indicated by a reduction in score.

[0242] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0243] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnias, assesses their frequency, and includes an assessment of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0244] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0245] A common questionnaire to assess sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc.cit.; Netzer et al., Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med. 1999 Oct 5;131(7):485-91). An appropriate recall period can also be selected.

[0246] Successful treatment is indicated by a reduction in score.

[0247] A common questionnaire to assess sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale (A.Shahid et al.,loc.cit.;Walters et al.;International Restless Legs Syndrome Study Group 2003. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Medicine 4(2),pp.121-132).

[0248] The therapeutic response can be assessed by a reduction in score.

[0249] Fatigue is commonly assessed, for example, by the FACES (Fatigue, Anergy, Consciousness, Energy, Sleepiness).

[0250] The FACES (Fatigue, Anergy, Consciousness, Vigor, Sleepiness) scale is a 50-item checklist to distinguish between tiredness, sleepiness, and fatigue. Respondents indicate the extent to which they have experienced each sensation or state of energy over the past week or another suitable recall period, using a scale ranging from 0 ("not at all") to 3 ("completely true"). Higher scores indicate more acute tiredness or fatigue states, except for items belonging to the Vigor subscale (A. Shahid et al., loc.cit.; Shapiro et al., Development of an adjective checklist to measure five FACES of fatigue and sleepiness. Data from a national survey of insomniacs. J Psychopomp Res. 2002 Jun;52(6):467-73).

[0251] Effective treatment reduces tiredness and / or fatigue scores and / or increases vitality subscale scores.

[0252] Treatment response can be assessed by using the above-mentioned quantitative measurements, such as polysomnography or actigraphy, and / or the above-mentioned questionnaires. Depending on the respective sleep scale, a significant decrease or increase in the total score, or a significant decrease in prevalence, frequency, and impact on daily function, respectively, indicates treatment-induced improvement of sleep disorders.

[0253] A common test to assess psychomotor retardation or aspects of it that can be used is the Salpêtrière Retardation Rating Scale (SRRS).

[0254] To enhance understanding of the ongoing pathophysiology and potential compensatory mechanisms, resting-state fMRI has been widely applied to patients with sleep disorders.

[0255] Alterations in the resting-state network can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0256] In insomnia patients, impaired functional connectivity has been observed within the default mode network (DMN) and the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Studies suggest that these networks contain important regions that integrate emotional and physical states, and that impaired functional connectivity within these networks and / or between these networks and other brain regions may underlie patients' alertness, subjective distress, and poor sleep continuity.

[0257] For example, sleep deprivation in healthy subjects leads to changes in functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these changes in brain functional connectivity resemble to some extent the vulnerability patterns of patients with Alzheimer's disease.

[0258] 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 alterations, and DMN functional connectivity correlates with self-reported sleepiness severity.

[0259] A study investigating the differences between night-shift and day-shift nurses found that circadian rhythm disorders contribute to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as speed and agility of response. Furthermore, the functional connectivity of the DMN is fundamentally different in early and late circadian phenotypes. As with other forms of sleep disorders, circadian rhythm disorders can lead to altered brain functional connectivity. Altered resting-state brain functional connectivity has been reported in a variety of diseases involving circadian rhythm disorders.

[0260] Although functional brain imaging is technically difficult to perform during a parasomnia event, differences in the precuneus have been observed in arousal disorders representing non-REM parasomnias.

[0261] The precuneus is involved in the analysis and integration of visual, auditory, and somatosensory information, as well as the monitoring of movement. The precuneus is a subregion of the DMN. Thus, in patients with parasomnia, the default mode network is affected.

[0262] Resting-state fMRI studies of patients suffering from sleep-related breathing disorders such as obstructive sleep apnea (OSA) have demonstrated that some of the main causes of OSA brain damage - chronic exposure to oxidative stress, intermittent hypoxia, hypocapnia and hypercapnia, and sleep fragmentation - can lead to significant global and regional connectivity deficits, especially in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems.

[0263] For example, sleep-related movement disorders such as periodic limb movements during sleep are reflected by alterations in the frontal motor control pathway, a subregion of the default mode network, and activity can be observed in the cerebellum and thalamus, in addition to activation in the red nucleus and brainstem.

[0264] In many cases, functional connectivity abnormalities in resting-state networks involved in sleep regulation are also implicated in psychomotor retardation, and thus, according to the invention, influencing those networks with the therapy according to the invention leads to amelioration of the sleep disorder and, if the treated patient suffers from psychomotor retardation, also leads to amelioration of psychomotor retardation.

[0265] Clinical data from studies of patients suffering from TRD or postpartum depression (PPD) support that sleep disorders can be successfully treated.

[0266] Studies involving administration of 5-MeO-DMT assessed, among other things, the MADRS item “reduced sleep,” which reflects insomnia.

[0267] The MADRS item "reduced sleep" refers to the experience of reduced duration or depth of sleep compared to a person's normal pattern when healthy. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects slight difficulty falling asleep or slightly reduced, light, or intermittent sleep. A score of 4 means reduced or interrupted sleep for at least 2 hours. A score of 6 means less than 2-3 hours of sleep.

[0268] The aggregated score for the MADRS item "Decreased Sleep" across all eight patients in the study group receiving the individualized dosing plan was a baseline of 25. One day after treatment (the earliest time point for assessing the effect of treatment on sleep), the score decreased to 12, corresponding to a 13-point or 52% improvement. Seven days after treatment, the score decreased to 9, corresponding to a 16-point or 64% improvement.

[0269] Scores for the MADRS item "Decreased sleep" across all four patients in the 12 mg group were compiled at baseline as 12. On the first post-treatment day, the score decreased to 10, corresponding to a 2-point or 17% improvement. On the seventh post-treatment day, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0270] Thus, the score for "reduced sleep", a scale item particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat patients suffering from sleep disorders, particularly psychiatric or nervous system disorders.

[0271] Treating a patient suffering from a sleep disorder, specifically insomnia, and associated psychomotor retardation, with 5-MeO-DMT or a pharma- ceutically acceptable salt thereof reduces or eliminates the psychomotor retardation and results in amelioration of the sleep disorder, specifically insomnia.

[0272] Reduction or elimination of psychomotor retardation in patients suffering from sleep disorders, specifically insomnia, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0273] The reduction or elimination of psychomotor retardation in a patient suffering from a sleep disorder, particularly insomnia, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a sleep disorder, particularly insomnia, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0274] The reduction or elimination of psychomotor retardation in a patient suffering from a sleep disorder, specifically insomnia, is reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0275] The reduction or elimination of psychomotor retardation in patients suffering from sleep disorders, particularly insomnia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from sleep disorders, particularly insomnia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0276] As mentioned above, psychomotor retardation is an important aspect in patients suffering from sleep disorder.Therefore, improving psychomotor retardation will also lead to improving sleep disorder.Since psychomotor retardation also affects other aspects of sleep disorder, we conclude that improving psychomotor retardation will further contribute to the overall improvement of sleep disorder, specifically insomnia.

[0277] In the case of idiopathic sleep disorders in patients also suffering from associated psychomotor retardation, the clinical response may be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S by at least one step. Preferably, the CGI-S decreases by at least two steps and / or to a score of 0. Particularly preferred is a decrease in the CGI-S by at least three steps and / or to a score of 0.

[0278] Improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S scores, is observed on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0279] The improvement of the idiopathic sleep disorder in the patient who also suffers from the associated psychomotor retardation, as reflected by a reduction in the CGI-S score of the patient who also suffers from the associated psychomotor retardation, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of the idiopathic sleep disorder in the patient who also suffers from the associated psychomotor retardation, as reflected by a reduction in the CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0280] In one embodiment, improvement of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S scores, is observed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and preferably persists for at least 14 days, and more preferably for at least 28 days.

[0281] In cases of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0282] In the case of idiopathic sleep disorder in a patient who also suffers from associated psychomotor retardation, improvement in the sleep disorder, as reflected by a reduction in the CGI-I score or PGI-I score of at least a "much improved" score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0283] Improvement in cases of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation may also be assessed by any other measure reflecting changes in quality or quantity of sleep, as described above, for example, the Pittsburgh Sleep Quality Index (PSQI).

[0284] When the PSQI is used to assess treatment outcome, success of treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0285] Improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI score, specifically to 5 or less, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, with the recall period extending from the time the acute hallucinatory experience subsided after the last administration to the time of evaluation.

[0286] Such improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, with the recall period spanning from the time the acute hallucinatory experience subsided after the last administration to the time of evaluation.

[0287] Improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI scores, is observed 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, with the recall period extending from the time the acute hallucinatory experience subsided after the last administration to the time of evaluation.

[0288] Psychomotor retardation and sleep disorder, particularly insomnia, are closely related to psychiatric and nervous system disorders.Psychomotor retardation and sleep disorder, particularly insomnia, occur in psychiatric or nervous system disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders caused by psychoactive substance use, such as substance use disorder (SUD), psychotic disorder, such as schizophrenia, dementia, such as Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's dementia, Parkinson's disease (PD), and chronic fatigue syndrome.

[0289] Treatment according to the invention results in improvement of both psychomotor retardation and sleep disorders, particularly insomnia, as well as associated psychiatric or nervous system disorders, examples of which are listed above.

[0290] Treatment of psychomotor retardation and mental and nervous system disorders In patients suffering from psychomotor retardation associated with a psychiatric or nervous system disorder, treatment of psychomotor retardation according to the invention results in an improvement of the condition associated with the psychomotor retardation.

[0291] Although psychomotor retardation may be considered a condition worthy of treatment regardless of other conditions, disorders, or symptoms that an individual may suffer from, some psychiatric and neurological disorders are associated with psychomotor retardation. Of note, the relationship between psychomotor retardation and psychiatric disorders is bidirectional. Not only does a psychiatric disorder have a negative impact on psychomotor retardation in patients, but psychomotor retardation may also be a contributing factor to the onset, progression, and prognosis of a psychiatric or neurological disorder.

[0292] In many cases, the resting state network involved in psychomotor retardation is also involved in the above conditions.

[0293] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption results in a reset of pathological brain connections as the networks reconnect. New healthy functional connections are established with lasting effects.

[0294] Disorders characterized by depressive episodes There are a number of disorders that are characterized by depressive episodes.

[0295] A depressive episode is a period of low mood and / or loss of pleasure in most activities.

[0296] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present during the same two-week period and representing a change from previous functioning, at least one of which is (1) depressed mood or (2) loss of interest or pleasure, and may include symptoms such as psychomotor retardation.

[0297] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0298] Psychomotor retardation occurs in patients suffering from disorders characterized by depressive episodes.

[0299] Psychomotor retardation is included as a diagnostic criterion for disorders characterized by depressive episodes. This may be assessed as part of the determination of the HAM-D or MADRS.

[0300] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0301] The items include apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal thoughts, and each item can be scored from 0 to 6. The total score can range from 0 to 60.

[0302] The MADRS item "Fatigue" describes difficulty in initiating movement or slowness in initiating and carrying out daily activities.

[0303] A score of 0 means that there is almost no difficulty in starting anything and no slowness. If the patient has difficulty starting activities, a score of 2 is assigned. A score of 4 means that simple daily activities are difficult to start and require effort to perform. In the case of complete fatigue, a score of 6 is assigned and the patient is unable to do anything without help.

[0304] This MADRS scale item is particularly relevant to psychomotor retardation (ie, decreased energy and activity, and decreased motivation).

[0305] The Hamilton Rating Scale for Depression (HAM-D) allows clinicians to assess the nature and severity of mood disorders in patient populations. The scale consists of 21 items for investigation, but only the first 17 items (low mood, guilt, suicide, initial insomnia, nighttime insomnia, delayed onset insomnia, work and interest, retardation, agitation, psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general symptoms, genital symptoms, hypochondriasis, weight loss, insight) are used for scoring.

[0306] For most questions, scores range from 0 to 4, with 4 representing more acute depressive symptoms. Some questions have a range down to 2. Total scores are tallied and can then be compared to previous scores or contrasted with a prescribed cut-off score.

[0307] In relation to the item "retardation", the questionnaire assesses slowness of thought and speech, poor concentration and reduced motor activity.

[0308] Psychomotor retardation in patients suffering from a disorder characterized by depressive episodes can be further assessed using, for example, the Salpêtrière Retardation Rating Scale (SRRS).

[0309] In patients suffering from disorders characterized by depressive episodes, altered functional connectivity has been observed within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal.

[0310] Treating a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the disorder characterized by depressive episodes.

[0311] Reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by depressive episodes is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0312] The reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by a depressive episode occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by a depressive episode preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0313] Reduction or elimination of psychomotor retardation in a patient suffering from a depressive episode, specifically a disorder characterized by fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0314] The reduction or elimination of psychomotor retardation in a patient suffering from a depressive episode, specifically a disorder characterized by fatigue, as reflected by an improvement in the MADRS item "fatigue" score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0315] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from a depressive episode, specifically a disorder characterized by retardation, is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0316] The reduction or elimination of psychomotor retardation in a patient suffering from a depressive episode, specifically a disorder characterized by retardation, as reflected by an improvement in the HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a depressive episode, specifically a disorder characterized by retardation, as reflected by an improvement in the HAM-D item retardation score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0317] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in a score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0318] The reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by depressive episodes, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0319] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0320] The reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0321] As mentioned above, psychomotor retardation is closely related to the disorder characterized by depressive episodes.Therefore, the improvement of psychomotor retardation will also lead to the improvement of the disorder characterized by depressive episodes.Because psychomotor retardation also affects other aspects of the disorder characterized by depressive episodes, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of the disorder characterized by depressive episodes.

[0322] Improvement in a disorder characterized by depressive episodes in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0323] The improvement of the disorder characterized by depressive episodes in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of the disorder characterized by depressive episodes in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0324] Major depressive disorder (MDD) is a mood disorder that causes persistent sadness and apathy. It affects how a person feels, thinks, and behaves and can cause a variety of emotional and physical problems.

[0325] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder.

[0326] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not improved sufficiently after at least two adequate treatment courses. Specifically, the patient has not improved sufficiently after at least two adequate treatment courses, where at least one of the two courses is a drug therapy, for example, the patient has not improved sufficiently after at least two adequate drug therapy courses. At least two past treatment courses were specifically carried out during the current depressive episode.

[0327] Psychomotor retardation is a central feature of major depressive disorder (MDD) and is one of the nine symptoms listed in the DSM-V to identify MDD.

[0328] Clinical symptoms of psychomotor retardation in MDD include, among others, speech abnormalities, reduced eye contact and eye movements, and poor posture.

[0329] The presence of psychomotor retardation may be useful in guiding treatment planning, as there may be evidence that tricyclic antidepressants (TCAs) may provide a greater response than selective serotonin reuptake inhibitors (SSRIs) in these cases.

[0330] Psychomotor retardation may be associated with greater symptom severity: a study of 291 patients with MDD found that patients with higher lifetime psychomotor retardation scores had more severe depression.

[0331] Psychomotor retardation in patients with MDD may be assessed as part of the determination of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, may be further assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0332] MDD can be characterized as a disorder involving impaired functional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, limbic network, and somatomotor network, where the functional connectivity is significantly different from that observed in healthy controls.

[0333] Treating patients suffering from MDD (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation, resulting in amelioration of the MDD.

[0334] Patients may have moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. Additionally, patients may have severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 25 or greater.

[0335] Reduction or elimination of psychomotor retardation in a patient suffering from MDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0336] The reduction or elimination of psychomotor retardation in a patient suffering from MDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from MDD preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0337] Reduction or elimination of psychomotor retardation in patients suffering from MDD, specifically fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0338] The reduction or elimination of psychomotor retardation in patients suffering from MDD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from MDD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0339] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from MDD, specifically psychomotor retardation, is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0340] The reduction or elimination of psychomotor retardation in patients suffering from MDD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from MDD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0341] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from MDD is reflected by an improvement in a score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0342] The reduction or elimination of psychomotor retardation in a patient suffering from MDD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from MDD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0343] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from MDD is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with at least motor retardation about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0344] The reduction or elimination of psychomotor retardation in patients suffering from MDD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from MDD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0345] As mentioned above, psychomotor retardation is closely related to MDD.Therefore, the improvement of psychomotor retardation will also lead to the improvement of MDD.Because psychomotor retardation also affects other aspects of MDD, we conclude that the improvement of psychomotor retardation, specifically the reduction or elimination of psychomotor retardation, will further contribute to the overall improvement of MDD.

[0346] Improvement in MDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0347] Improvement in MDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in MDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0348] In comparison to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to patients suffering from MDD associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0349] Preferably, patients suffering from MDD associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0350] Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings that include emotional lows (major depressive episodes) and emotional highs (manic or hypomanic episodes). Bipolar disorder is a relapsing, chronic illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0351] BD is classified as bipolar I disorder if there has been at least one manic episode with or without a depressive episode. BD is classified as bipolar II disorder if there has been at least one hypomanic episode (without a full manic episode) and one major depressive episode. If these symptoms are due to drugs or medical problems, they are not diagnosed as bipolar disorder.

[0352] Patients suffering from BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0353] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not improved sufficiently after at least two adequate treatment courses. Specifically, the patient has not improved sufficiently after at least two adequate treatment courses, where at least one of the two courses is a drug therapy, for example, the patient has not improved sufficiently after at least two adequate drug therapy courses. At least two past treatment courses were specifically carried out during the current depressive episode.

[0354] Psychomotor retardation is a central feature of bipolar depression and is one of nine symptoms listed in the DSM-V to identify a major depressive episode in the context of bipolar disorder.

[0355] A study comparing patients with bipolar depression with age-matched patients with unipolar depression found that bipolar disorder was associated with higher psychomotor retardation scores than unipolar depression at the same depression severity scores.

[0356] Psychomotor retardation in patients suffering from BD may be assessed as part of the determination of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, may be further assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0357] Patients suffering from bipolar disorder display characteristic intrinsic organization and interconnection abnormalities of resting-state networks.

[0358] Compared to healthy controls, resting-state functional magnetic resonance imaging studies demonstrated altered functional connectivity in specific regions within and / or between the default mode network, the salience network, and the central executive network.

[0359] Treating patients suffering from BD (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation, resulting in improvement of BD.

[0360] Typically, patients with BD, whether diagnosed with bipolar II or bipolar I disorder, are currently suffering from a major depressive episode.

[0361] The severity of the current major depressive episode may be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient's total score may be 19 or greater, such as 24 or greater, particularly 37 or greater.

[0362] Reduction or elimination of psychomotor retardation in patients suffering from BD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0363] The reduction or elimination of psychomotor retardation in a patient suffering from BD occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from BD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0364] Reduction or elimination of psychomotor retardation in patients suffering from BD, specifically fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0365] The reduction or elimination of psychomotor retardation in patients suffering from bipolar disorder, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from BD, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0366] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from BD, specifically retardation, is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0367] The reduction or elimination of psychomotor retardation in patients suffering from BD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from BD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0368] Alternatively or additionally, reduction in psychomotor retardation in a patient suffering from BD is reflected by an improvement in a score on the Salpêtrière Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof.

[0369] The reduction or elimination of psychomotor retardation in a patient suffering from BD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from BD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0370] Alternatively or additionally, reduction in psychomotor retardation in a patient suffering from BD is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with at least motor retardation about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0371] The reduction or elimination of psychomotor retardation in patients suffering from BD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from BD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0372] As mentioned above, psychomotor retardation is closely related to BD. Therefore, the improvement of psychomotor retardation will also lead to the improvement of BD. Because psychomotor retardation also affects other aspects of BD, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of BD.

[0373] Improvement in BD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0374] Improvement in BD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in BD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0375] In comparison to other hallucinogens such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to patients suffering from bipolar disorders associated with psychomotor retardation, e.g., bipolar I disorder and bipolar II disorder, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0376] Preferably, patients suffering from bipolar disorders associated with psychomotor retardation, such as bipolar I disorder and bipolar II disorder, do not experience treatment-emergent mania or hypomania.

[0377] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within 4 weeks of giving birth. Some women may develop PPD, while over 50% of women experience a short period of low mood or tearfulness after giving birth. Epidemiological studies estimate the prevalence of PPD to be around 15%.

[0378] Patients with PPD may have a treatment-resistant form of the disorder.

[0379] Postpartum depression is also defined as a major depressive episode within 4 weeks after delivery. Psychomotor retardation is therefore a central feature of postpartum depression and is one of the nine symptoms listed in the DSM-V to identify a major depressive episode.

[0380] Psychomotor retardation in patients with PPD may be assessed as part of the determination of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, may be further assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0381] In patients with PPD, significant changes in neural activity are observed in brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with impaired functional connectivity of resting-state networks, such as the default mode network and frontoparietal networks, and / or between them.

[0382] Treating patients suffering from PPD (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the PPD.

[0383] Patients may have moderate or severe PPD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. Additionally, patients may have severe PPD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0384] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0385] Additionally, patients treated according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0386] Still further, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0387] Reduction or elimination of psychomotor retardation in patients suffering from PPD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0388] The reduction or elimination of psychomotor retardation in a patient suffering from PPD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from PPD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0389] Reduction or elimination of psychomotor retardation in patients suffering from PPD, specifically fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0390] The reduction or elimination of psychomotor retardation in patients suffering from PPD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from PPD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0391] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from PPD, specifically retardation, is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0392] The reduction or elimination of psychomotor retardation in patients suffering from PPD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from PPD, specifically retardation, as reflected by an improvement in HAM-D item retardation score, preferably persists until at least 6 days, specifically until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0393] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PPD is reflected by an improvement in a score on the Salpetriere Retardation Scale at least about 2 hours after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof.

[0394] The reduction or elimination of psychomotor retardation in a patient suffering from PPD, as reflected by at least an improvement in the score on the Salpetriere Retardation Scale, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from PPD, as reflected by at least an improvement in the score on the Salpetriere Retardation Scale, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0395] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from PPD is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with at least motor retardation about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0396] The reduction or elimination of psychomotor retardation in patients with PPD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients with PPD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0397] As mentioned above, psychomotor retardation is closely related to PPD.Therefore, the improvement of psychomotor retardation will also lead to the improvement of PPD.Because psychomotor retardation also affects other aspects of PPD, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of PPD.

[0398] Improvement in PPD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0399] Improvement in PPD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in PPD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0400] Furthermore, psychomotor retardation impairs maternal functioning.

[0401] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Function (BIMF). This index was designed to measure functioning during the first year after delivery. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6, resulting in a maximum total score of 120. The higher the score, the better the assessment of maternal functioning.

[0402] The BIMF identifies the main areas of functioning for mothers in the postnatal period as self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, control, and adjustment.

[0403] A BIMF score of 95 or less is considered herein to represent slight maternal dysfunction, a score of 80 or less is considered herein to represent maternal dysfunction, and a score of 65 or less is considered herein to represent severe maternal dysfunction.

[0404] The inventors determined that increased scores on the MADRS item "Fatigue" adversely affected both aspects of maternal functioning (maternal ability related to interacting with infant(s) and maternal self-care).

[0405] An increase in the score on the MADRS item "Fatigue" impairs self-care, psychological well-being, and control. Conversely, an improvement on this MADRS item translates to an improvement in maternal functioning, specifically the BIMF functioning domains psychological well-being, social support, and / or control.

[0406] We conclude that 5-MeO-DMT can be used to treat PPD patients to achieve improvement in psychomotor retardation, specifically, reducing or eliminating fatigue.

[0407] We further conclude that reducing or eliminating fatigue by treating patients with PPD not only results in a decrease in the MADRS total score, but also in improved maternal functioning, as reflected by an increase in the BIMF score.

[0408] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0409] Improved maternal function in patients with PPD is reflected by at least an improvement in the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0410] Improved maternal function in patients with PPD, as reflected by at least an improvement in BIMF total score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improved maternal function, as reflected by at least an improvement in BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0411] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to patients suffering from PPD associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0412] Preferably, patients suffering from PPD associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0413] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms often beginning in the fall and remitting in the spring. Many people experience sadness, hopelessness, lack of interest in activities, fatigue, and social withdrawal.

[0414] Patients suffering from seasonal affective disorder may have a treatment-resistant form of the disorder.

[0415] Compared to controls, patients with seasonal affective disorder show significant season-independent impairments in tasks measuring working memory, cognitive processing speed, and motor speed.

[0416] Sensorimotor impairments have been reported in depressed subjects compared with healthy controls.

[0417] Psychomotor symptoms associated with depressed mood are often thought to affect not only the execution of motor responses but also the speed of thought.

[0418] Seasonal affective disorder is associated with psychomotor retardation as depressive episodes may meet DSM-V criteria for a major depressive episode.

[0419] Psychomotor retardation in patients suffering from seasonal affective disorder may be assessed as part of the determination of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, may be further assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0420] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0421] Treating patients suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the seasonal affective disorder.

[0422] Reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0423] The reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0424] Reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder, specifically fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0425] The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0426] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0427] The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, specifically retardation, as reflected by an improvement in the HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, specifically retardation, as reflected by an improvement in the HAM-D item retardation score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0428] Alternatively or additionally, the reduction in psychomotor retardation in a patient suffering from seasonal affective disorder is reflected by an improvement in a score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0429] The reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder, as reflected by at least an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder, as reflected by at least an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0430] Alternatively or additionally, reduction in psychomotor retardation in a patient suffering from seasonal affective disorder is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale related to motor retardation at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0431] The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0432] As mentioned above, psychomotor retardation is closely related to seasonal affective disorder.Therefore, the improvement of psychomotor retardation will also lead to the improvement of seasonal affective disorder.Because psychomotor retardation also affects other aspects of seasonal affective disorder, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of seasonal affective disorder.

[0433] Improvement in seasonal affective disorder in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0434] The improvement of seasonal affective disorder in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of seasonal affective disorder in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0435] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to patients suffering from seasonal affective disorder associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0436] Preferably, patients suffering from seasonal affective disorder associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0437] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. Persistent depressive disorder is diagnosed when depressive symptoms are present for the majority of days over a period of at least two years. Symptom-free periods are less than two months.

[0438] While depressed, two or more of the following should be present: 1. Hopelessness, 2. Low energy or fatigue, 3. Low self-esteem, 4. Decreased (insomnia) or increased (hypersomnia) sleep, 5. Loss of appetite or overeating, 6. Difficulty making decisions or difficulty concentrating.

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

[0440] According to the DSM-V, persistent depressive disorder is characterized by criteria for major depressive disorder that have been present continuously for two years.

[0441] Persistent depressive disorder is associated with psychomotor retardation as depressive episodes may meet DSM-V criteria for a major depressive episode.

[0442] Psychomotor retardation in patients suffering from PDD may be assessed as part of the determination of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, may be further assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0443] In patients suffering from persistent depressive disorder, alterations in functional connectivity are observed within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal.

[0444] Functional connectivity impairments are observed within and between the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0445] Treating patients suffering from PDD (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the PDD.

[0446] Reduction or elimination of psychomotor retardation in a patient suffering from PDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0447] The reduction or elimination of psychomotor retardation in a patient suffering from PDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from PDD preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0448] Reduction or elimination of psychomotor retardation in patients suffering from PDD, specifically fatigue, is reflected by an improvement in the score for at least the MADRS item "Fatigue" about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0449] The reduction or elimination of psychomotor retardation in patients suffering from PDD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from PDD, specifically fatigue, as reflected by an improvement in the MADRS item "fatigue" score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0450] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PDD, specifically psychomotor retardation, is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0451] The reduction or elimination of PDD, specifically psychomotor retardation in patients suffering from retardation, as reflected by an improvement in HAM-D item retardation score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of PDD, specifically psychomotor retardation in patients suffering from retardation, as reflected by an improvement in HAM-D item retardation score, preferably persists until at least 6 days, specifically at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0452] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PDD is reflected by an improvement in a score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0453] The reduction or elimination of psychomotor retardation in a patient suffering from PDD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from PDD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0454] Alternatively or additionally, reduction or elimination of psychomotor retardation in a patient suffering from PDD is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with at least motor retardation about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0455] The reduction or elimination of psychomotor retardation in patients with PDD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients with PDD, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0456] As mentioned above, psychomotor retardation is closely related to PDD.Therefore, the improvement of psychomotor retardation will also lead to the improvement of PDD.Because psychomotor retardation also affects other aspects of PDD, we conclude that the improvement of psychomotor retardation, specifically the reduction or elimination of psychomotor retardation, will further contribute to the overall improvement of PDD.

[0457] Improvement in PDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0458] Improvement in PDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in PDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0459] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to a patient suffering from a persistent depressive disorder associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0460] Preferably, patients suffering from persistent depressive disorder associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0461] Mental and behavioral disorders due to psychoactive substance use Substance use disorders (SUDs) are mental disorders that affect a person's behavior and result in an inability to control their use of substances, such as legal or illegal drugs, alcohol, or medication. Symptoms range from moderate to severe, with addiction being the most severe form of SUD.

[0462] Patients suffering from SUD may suffer from treatment-resistant forms of the disorder.

[0463] Psychomotor retardation occurs in patients suffering from certain mental and behavioral disorders that result from psychoactive substance use.

[0464] Psychomotor retardation has been observed in methamphetamine withdrawal, and one study showed that female patients with methamphetamine use disorder were more likely to experience psychomotor retardation than male users.

[0465] A large study of frequent cannabis users found that psychomotor retardation was one of the most common symptoms of cannabis withdrawal, although the lifetime prevalence was only 1%.

[0466] Resting-state functional connectivity (rsFC) has been found to be altered in patients with psychomotor retardation as well as in patients with SUD.

[0467] Psychomotor retardation, or at least aspects thereof, may be assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS).

[0468] Treating patients suffering from SUD (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation, resulting in amelioration of the SUD.

[0469] Reduction or elimination of psychomotor retardation in a patient suffering from a SUD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0470] The reduction or elimination of psychomotor retardation in a patient suffering from a SUD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a SUD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0471] Reduction or elimination of psychomotor retardation in a patient suffering from a SUD is reflected by an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0472] The reduction or elimination of psychomotor retardation in a patient suffering from a SUD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a SUD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0473] As mentioned above, psychomotor retardation is an important aspect in patients suffering from SUD. Therefore, improving psychomotor retardation will also lead to improvement of SUD. Because psychomotor retardation also affects other aspects of SUD, we conclude that improving psychomotor retardation will further contribute to the overall improvement of substance use disorder.

[0474] Improvement in SUD in patients suffering from psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0475] Improvement in psychomotor retardation in a patient suffering from SUD, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in psychomotor retardation in a patient suffering from SUD, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0476] Psychotic disorders Psychotic disorders are severe mental disorders that cause abnormal thinking and perception. Psychotic disorders are characterized by positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking (typically manifested as disorganized speech), severely disorganized behavior, and experiences of passivity and dominance, negative symptoms such as blunted or flat affect and amotivation, and significant reality testing disorders and behavioral changes that manifest in psychomotor disorders.

[0477] Patients suffering from a psychotic disorder may suffer from a treatment-resistant form of the disorder.

[0478] The DSM-V describes symptoms of psychomotor retardation, such as lack of verbal and motor responses, as a core feature defining a psychotic disorder. Schizophrenia is an example of a primary psychotic disorder in which psychomotor retardation is a prominent feature.

[0479] Psychomotor retardation is also seen in other psychotic disorders, such as schizoaffective disorder.

[0480] Psychomotor retardation or at least aspects thereof may be further assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0481] Brain imaging of patients suffering from psychosis by functional magnetic resonance imaging of the brain resting state network reveals significant alterations in distinct regions within and / or between the central executive network, the default mode network, and the salience network. Alterations in the resting state network can be identified even in patient populations at risk for psychosis.

[0482] Treating a patient suffering from a psychotic disorder (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the psychotic disorder.

[0483] Reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0484] The reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0485] The reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder is reflected by an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0486] The reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0487] As mentioned above, the occurrence of psychomotor retardation is an important disease aspect in patients suffering from psychotic disorder.Therefore, the improvement of psychomotor retardation will also lead to the improvement of psychotic disorder.Since psychomotor retardation also affects other aspects of psychotic disorder, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of psychotic disorder.

[0488] Improvement in the psychotic disorder in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0489] The improvement of the psychotic disorder in the patient who also suffers from the associated psychomotor retardation, as reflected by a reduction in the CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of the psychotic disorder in the patient who also suffers from the associated psychomotor retardation, as reflected by a reduction in the CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0490] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to a patient suffering from a psychotic disorder characterized by mania or hypomania and associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0491] Preferably, patients suffering from a psychotic disorder characterized by mania or hypomania and associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0492] Schizophrenia is a severe mental health condition characterised by disturbances in multiple psychomodalities including perception, self-experience, volition, emotion and behaviour. Psychomotor disturbances, including catatonia, may be present.

[0493] Patients suffering from schizophrenia may suffer from a treatment-resistant form of the disorder.

[0494] Psychomotor retardation and slowing is also a central feature of schizophrenia and is classified as one of the "negative symptoms" that characterize the disease. Symptoms can range from slowed movements to severe catatonia.

[0495] There is evidence to suggest that psychomotor retardation is associated with more severe illness, as well as decline in semantic and episodic memory in schizophrenia.

[0496] Resting-state functional connectivity abnormalities, specifically within and / or between the default mode network, the frontoparietal network, and the salience network, have been reported in individuals with schizophrenia.

[0497] Psychomotor retardation or at least aspects thereof may be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0498] Treating patients suffering from schizophrenia (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of schizophrenia.

[0499] Reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0500] The reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0501] The reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia is reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0502] The reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0503] As mentioned above, psychomotor retardation is closely related to schizophrenia.Therefore, the improvement of psychomotor retardation will also lead to the improvement of schizophrenia.Because psychomotor retardation also affects other aspects of schizophrenia, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of schizophrenia.

[0504] Improvement in schizophrenia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0505] The improvement of schizophrenia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of schizophrenia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0506] In comparison to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can be administered to a patient suffering from schizophrenia associated with psychomotor retardation, preferably using the administration schemes described herein, without significant risk of inducing mania or hypomania.

[0507] Preferably, patients suffering from schizophrenia associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0508] Dementia Dementia is caused by abnormal brain changes that induce cognitive decline and affect behavior, emotions and relationships. The condition is generally characterized by a loss of memory, language, problem-solving and other thinking skills severe enough to interfere with daily life.

[0509] Psychomotor slowing is a key feature in dementia syndromes.

[0510] Psychomotor retardation or at least aspects thereof may be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0511] Dementia affects various functional and structural connectivity networks in the brain, which can be demonstrated by magnetic resonance imaging studies: alterations are observed within and / or between the default mode network (DMN), the salience network, and the central executive network (CEN).

[0512] Treating a patient suffering from dementia and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the dementia.

[0513] Reduction or elimination of psychomotor retardation in a patient suffering from dementia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0514] The reduction or elimination of psychomotor retardation in a patient suffering from dementia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from dementia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0515] The reduction or elimination of psychomotor retardation in a patient suffering from dementia is reflected by an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0516] The reduction or elimination of psychomotor retardation in a patient suffering from dementia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from dementia, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0517] As mentioned above, psychomotor retardation occurs in patients suffering from dementia.Therefore, improving psychomotor retardation will also lead to improving dementia.Since psychomotor retardation also affects other aspects of dementia, we conclude that improving psychomotor retardation will further contribute to the overall improvement of dementia.

[0518] Improvement in dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0519] The improvement in dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement in dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0520] Alzheimer's dementia (AD) is a widespread neurodegenerative disorder with an insidious onset and slow progression of cognitive impairment. The percentage of neurocognitive impairment attributable to Alzheimer's disease ranges from approximately 60% to over 90%, depending on the contextual and diagnostic criteria. Decline in learning and memory is the primary early feature, and the decline is progressive.

[0521] Psychomotor slowing is a key feature in dementia syndromes such as Alzheimer's disease. The pathological cause may be slower sensorimotor and decision processes.

[0522] A study of 148 patients with mild cognitive impairment and age-matched controls found that the presence of psychomotor retardation significantly increases the risk of conversion to Alzheimer's disease dementia.

[0523] Psychomotor retardation or at least aspects thereof may be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0524] AD affects various functional and structural connectivity networks in the brain that are associated with the topography, clinical phenotype, and severity of the disease. Magnetic resonance imaging studies have demonstrated continuous structural and functional disconnections between brain regions that support the idea that AD is a disconnection syndrome. Specifically, alterations within and / or between the default mode network (DMN), salience network, and central executive network (CEN) are observed in both patients with AD and individuals at high risk of developing AD.

[0525] Thus, affecting those networks by the therapy according to the present invention leads to an improvement in psychomotor retardation and also to an improvement in the symptoms of AD.

[0526] Treatment of patients suffering from AD and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of Alzheimer's dementia.

[0527] Reduction or elimination of psychomotor retardation in patients suffering from AD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0528] The reduction or elimination of psychomotor retardation in a patient suffering from AD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from AD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0529] Reduction or elimination of psychomotor retardation in a patient suffering from AD is reflected by an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0530] The reduction or elimination of psychomotor retardation in a patient suffering from AD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from AD, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0531] As mentioned above, psychomotor retardation is an important aspect in patients suffering from AD.Therefore, the improvement of psychomotor retardation will also lead to the improvement of AD.Since psychomotor retardation also affects other aspects of AD, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of AD.

[0532] Improvement in AD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0533] Improvement of AD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement of AD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0534] Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and the regulation of automatic body functions.

[0535] Psychomotor slowing plays an important role in dementia with Lewy bodies (DLB). In DLB, psychomotor slowing may be due to the contribution of visual and attention disorders that also contribute to hallucinations. DLB is characterized by worse psychomotor impairment than Alzheimer's disease.

[0536] Psychomotor retardation or at least aspects thereof may be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0537] Alterations in resting-state networks (RSNs) can be identified in patients with DLB. Functional MRI studies show alterations in functional connectivity within and / or between the default mode network, salience network, executive network, and basal ganglia / limbic network.

[0538] Treating patients suffering from DLB and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation, resulting in amelioration of DLB.

[0539] Reduction or elimination of psychomotor retardation in patients suffering from DLB is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0540] The reduction or elimination of psychomotor retardation in a patient suffering from DLB occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from DLB preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0541] Reduction or elimination of psychomotor retardation in a patient suffering from DLB is reflected by an improvement in the Salpêtrière Retardation Rating Scale (SRRS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0542] The reduction or elimination of psychomotor retardation in patients suffering from DLB, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from DLB, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0543] As mentioned above, psychomotor retardation is an important aspect in patients suffering from DLB.Therefore, improving psychomotor retardation will also lead to the improvement of DLB.Because psychomotor retardation also affects other aspects of DLB, we conclude that improving psychomotor retardation will further contribute to the overall improvement of DLB.

[0544] Improvement in DLB in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0545] Improvement in DLB in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Improvement in DLB in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0546] Vascular dementia is a common type of dementia characterized by problems with reasoning, planning, judgment, memory, and other thought processes. These problems are caused by brain damage due to impaired blood flow to the brain.

[0547] Psychomotor retardation is highlighted as a clinical feature consistent with a probable diagnosis of vascular dementia according to the NINDS-AIREN (National Institute of Neurological Disorders and Stroke / Association Internationale pour la Recherche et l'Enseignement en Neurosciences research) criteria.

[0548] Psychomotor retardation occurs particularly frequently when vascular dementia affects subcortical regions.

[0549] Psychomotor retardation, or at least aspects thereof, may be assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS).

[0550] Functional magnetic resonance imaging reveals altered functional connectivity of resting-state networks after cerebrovascular injury. Patients suffering from severe or mild vascular neurocognitive impairment show functional connectivity abnormalities within the DMN and other resting-state networks.

[0551] Treating patients suffering from vascular dementia and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the vascular dementia.

[0552] Reduction or elimination of psychomotor retardation in patients suffering from vascular dementia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0553] The reduction or elimination of psychomotor retardation in a patient suffering from vascular dementia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from vascular dementia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0554] The reduction or elimination of psychomotor retardation in a patient suffering from vascular dementia is reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0555] The reduction or elimination of psychomotor retardation in patients suffering from vascular dementia, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from vascular dementia, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0556] As mentioned above, psychomotor retardation is an important aspect in patients suffering from vascular dementia.Therefore, improving psychomotor retardation will also lead to the improvement of vascular dementia.Since psychomotor retardation also affects other aspects of vascular dementia, we conclude that improving psychomotor retardation will further contribute to the overall improvement of vascular dementia.

[0557] Improvement in vascular dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0558] The improvement of vascular dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of vascular dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0559] Parkinson's dementia is characterized by slowly progressive problems with movement and changes in thinking and behavior in patients diagnosed with Parkinson's disease, a disease most commonly associated with slowing of movement, resting tremor, and gait instability that can lead to falls.

[0560] Parkinson's disease dementia is also associated with psychomotor retardation.

[0561] Research has shown that there is a functional reorganization of resting-state networks in patients with Parkinson's disease dementia, which is important for generating and maintaining efficient behavioral and cognitive abilities. Levodopa, which improves the clinical condition of Parkinson's disease patients, may affect the functional connectivity of the resting-state network in Parkinson's disease patients.

[0562] Treating a patient suffering from Parkinson's disease dementia and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of Parkinson's disease dementia.

[0563] Reduction or elimination of psychomotor retardation in patients suffering from Parkinson's disease dementia is observed on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0564] The reduction or elimination of psychomotor retardation in a patient suffering from Parkinson's disease dementia occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from Parkinson's disease dementia preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0565] Improvement in psychomotor retardation in patients suffering from Parkinson's disease dementia, as reflected by a reduction in CGI-S score, is observed on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0566] The improvement in psychomotor retardation in patients with Parkinson's disease dementia, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement in psychomotor retardation in patients with Parkinson's disease dementia, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0567] Reduction or elimination of psychomotor retardation in a patient suffering from Parkinson's disease dementia is reflected by an improvement in the Salpêtrière Retardation Rating Scale (SRRS) score on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0568] The reduction or elimination of psychomotor retardation in patients suffering from Parkinson's disease dementia, as reflected by an improvement in the score of the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from PDD, as reflected by an improvement in the Salpêtrière Retardation Rating Scale (SRRS), preferably lasts for at least 6 days, particularly at least 14 days, more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0569] As mentioned above, psychomotor retardation is an important aspect in patients suffering from Parkinson's disease dementia.Therefore, improving psychomotor retardation will also lead to the improvement of Parkinson's disease dementia.Since psychomotor retardation also affects other aspects of Parkinson's disease dementia, we conclude that improving psychomotor retardation will further contribute to the overall improvement of Parkinson's disease dementia.

[0570] Improvement in Parkinson's disease dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof.

[0571] The improvement of Parkinson's disease dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of Parkinson's disease dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0572] Parkinson's disease Parkinson's disease (PD) is a disease characterized by slowly progressive problems with movement, and most commonly involves slowing of movement, resting tremor, and gait instability that can lead to falls.

[0573] Psychomotor retardation is a cardinal feature of subcortical disorders such as Parkinson's disease (PD).

[0574] Psychomotor retardation or at least aspects thereof may be assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Digit Symbol Substitution Test (DSST).

[0575] Analysis of resting-state networks using functional magnetic resonance imaging indicates that Parkinson's disease-related cognitive impairment is associated with altered connectivity patterns within and / or between resting-state functional connectivity networks, such as the default mode network, the dorsal attention network, or the frontoparietal network.

[0576] Treating patients suffering from PD and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation, resulting in improvement of PD.

[0577] Reduction or elimination of psychomotor retardation in patients suffering from PD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0578] The reduction or elimination of psychomotor retardation in a patient suffering from PD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from PD preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0579] Reduction or elimination of psychomotor retardation in a patient suffering from PD is reflected by an improvement in the Salpêtrière Retardation Rating Scale (SRRS) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0580] The reduction or elimination of psychomotor retardation in patients with PD, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients with PD, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0581] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PD is reflected by an improvement in at least a Digit Symbol Substitution Test (DSST) score about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0582] The reduction or elimination of psychomotor retardation in patients with PD, as reflected by an improvement in the Digit Symbol Substitution Test (DSST) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients with PD, as reflected by an improvement in the Digit Symbol Substitution Test (DSST) score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0583] As mentioned above, psychomotor retardation is an important aspect in patients suffering from PD.Therefore, the improvement of psychomotor retardation will also lead to the improvement of PD.Since psychomotor retardation also affects other aspects of PD, we conclude that the improvement of psychomotor retardation will further contribute to the overall improvement of PD.

[0584] Improvement in psychomotor retardation in patients with PD, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0585] The improvement in psychomotor retardation in patients suffering from PD, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement in psychomotor retardation in patients suffering from PD, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0586] Chronic fatigue syndrome Fatigue refers to feelings of exhaustion, weariness, and reduced energy. Fatigue is experienced as a weakening or depletion of physical or mental resources. Although considered normal after periods of mental or physical exertion, fatigue can also occur in the absence of such exertion as a symptom of a health condition.

[0587] Furthermore, chronic fatigue that is exacerbated by activity is a prominent symptom in chronic fatigue syndrome, a disorder in which severe fatigue is accompanied by neurocognitive, autonomic, and immunological symptoms.

[0588] Various abnormalities in normal sleep patterns have been reported in patients with chronic fatigue syndrome that may act as perpetuating factors.

[0589] Symptoms of chronic fatigue syndrome also include psychomotor slowing.

[0590] Patients suffering from chronic fatigue syndrome exhibit abnormalities in resting-state functional connectivity, which correlates significantly with the severity of chronic fatigue.

[0591] Treating patients suffering from chronic fatigue syndrome (including treatment-resistant forms of the disorder) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and results in amelioration of the chronic fatigue syndrome.

[0592] Reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0593] The reduction or elimination of psychomotor retardation in a patient suffering from chronic fatigue syndrome occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in a patient suffering from chronic fatigue syndrome preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0594] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from chronic fatigue syndrome is reflected by an improvement in the score on the Salpetriere Retardation Rating Scale (SRRS) at least about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, on the first day, e.g., about 24 hours, on the seventh day, on the fourteenth day, and / or on the twenty-eighth day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0595] The reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0596] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from chronic fatigue syndrome is reflected by an improvement in the mean score on the Motor Agitation and Retardation Scale (MARS) subscale associated with at least motor retardation about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0597] The reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome, as reflected by an improvement in the mean scores on at least the Motor Agitation and Retardation Scale (MARS) subscales associated with motor retardation, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0598] As mentioned above, psychomotor retardation is closely related to chronic fatigue syndrome.Therefore, improving psychomotor retardation will also lead to improving chronic fatigue syndrome.Because psychomotor retardation also affects other aspects of chronic fatigue syndrome, we conclude that improving psychomotor retardation, specifically reducing or eliminating psychomotor retardation, will further contribute to the overall improvement of chronic fatigue syndrome.

[0599] Improvement in chronic fatigue syndrome in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, 1 day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0600] The improvement of chronic fatigue syndrome in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of chronic fatigue syndrome in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists until at least 6 days, particularly until at least 14 days, and more preferably until at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0601] The following examples are included to aid in the understanding of the invention and are not intended, and should not be construed as, limiting the invention, as set forth in the claims which follow, in any manner.

[0602] Example 1 – Generation and administration of 5-MeO-DMT aerosol Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask such that the target dose of 5-MeO-DMT free base to be administered to a subject or patient by inhalation is contained in a volume of 200 μl. A typical target dosage of 5-MeO-DMT is 1 mg to 25 mg. For example, if the target dose of 5-MeO-DMT is 18 mg, then 90 mg of 5-MeO-DMT would be dissolved in 100% ethanol to a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until the time of use.

[0603] Step 2: 200 μl of the solution is transferred into a dosing capsule containing a drip pad (Storz & Bickel, Germany) and the dosing capsule is then closed with its lid.

[0604] Step 3: The dosing capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of the first Volcano Medic Vaporizer, which has been preheated with the temperature set to 55°C. The vaporizer airflow is then turned on for 60 seconds at a pre-set flow rate of approximately 12 l / min. The heated air flows into the dosing capsule, evaporating the ethanol and leaving the target dose of 5-MeO-DMT in the capsule as a thin layer covering the stainless steel wire mesh. It can be confirmed that the dosing capsule has been correctly prepared by demonstrating that the final weight increase of the capsule compared to the weight of the empty capsule is approximately equal to the target dose of 5-MeO-DMT.

[0605] Step 4: The prepared dose capsule is removed from the filling chamber. The dose capsule is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which is preheated by setting the temperature at 210° C. and has the airflow turned on for at least 5 minutes and turned off immediately before transferring the capsule. A valved inhalation balloon (Storz & Bickel, Germany) is attached to the socket of the filling chamber, the filling chamber is tightly closed, and immediately thereafter the airflow is turned on for exactly 15 seconds at a pre-set flow rate of about 12 l / min and then turned off. This aerosolizes the entire dose of 5-MeO-DMT and disperses it in the approximately 3 liters of air in the inhalation balloon. It can be confirmed that the 5-MeO-DMT has been accurately aerosolized by demonstrating that the weight of the capsule has returned approximately to its initial weight.

[0606] Step 5: The balloon is then removed from the filling chamber, the valve automatically closes, a mouthpiece is attached to the balloon, and the aerosol is ready to be administered to the subject or patient.

[0607] Step 6: In preparation for administration, the patient is asked to first inhale deeply and exhale completely 1-2 times, and then finish this sequence with a deep exhale. Then, holding the mouthpiece firmly against the lips, inhale the entire volume of the inhalation balloon completely in one inhalation, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0608] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO2020 / 169850 A1, the contents of which are incorporated herein by reference.

[0609] Example 2 – Preparation of high purity 5-MeO-DMT 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 vol) at 35-40°C and then cooled to room temperature over 30 min. After stirring at room temperature for 50 min, no crystallization was observed, so the batch temperature was reduced to 7-12°C over 30 min. Crystallization occurred after stirring at 7-12°C for 10 min. The batch was then stirred at 7-12°C for 1 h before being filtered. After washing with MTBE (1 mL, 0.5 vol), the batch was dried under vacuum at 7-12°C for 3.5 h to give 1.02 g (50% recovery) of a pale orange solid. The isolated solid was analyzed for purity by HPLC as described in WO2020 / 169850 A1. The purity was found to be 99.74% area.

[0610] The analytical results further indicate that the individual impurity levels were less than 0.10% area. Solvent analysis of the sample indicated the MTBE level was 17 ppm.

[0611] Example 3 – Preparation of 5-MeO-DMT hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0612] The free base of 5-MeO-DMT was mixed with isopropyl acetate (10 volumes) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr was charged in a single aliquot (1 M in ethanol, 1 equivalent). The mixture was maintained at temperature and equilibrated for 3 hours.

[0613] After 1 hour, a suspension formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuum at 40° C. for 18 hours.

[0614] An off-white crystalline material was obtained.

[0615] The salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern including peaks at 14.5°2θ ± 0.2°2θ, 16.7°2θ ± 0.2°2θ, 17.0°2θ ± 0.2°2θ, 20.6°2θ ± 0.2°2θ, 20.7°2θ ± 0.2°2θ, 21.4°2θ ± 0.2°2θ, 24.2°2θ ± 0.2°2θ, 24.8°2θ ± 0.2°2θ, 25.3°2θ ± 0.2°2θ, and 27.4°2θ ± 0.2°2θ measured using Cu Kα radiation.

[0616] Example 4 – Determination of inhibition constants for central 5-HT1A and 5-HT2A receptors in postmortem human brain membrane preparations In this study, the affinity of three hallucinogenic test compounds (psilocin, DMT and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue from the hippocampus and frontal cortex, respectively, was determined using radioligand binding techniques.

[0617] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors had died suddenly, had no history of coma, psychiatric or neurological disorders, were under 65 years of age, and samples were obtained within 72 hours of death.

[0618] Binding to 5-HT1A receptors in postmortem human hippocampus The hippocampi were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was kept on ice and the pellet was rehomogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold membrane preparation buffer (1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 min, followed by centrifugation at 20,500 g for 10 min. The pellet was resuspended and centrifuged a final time (20,500 x g, 10 min) to wash the tissue. The resulting pellet was then resuspended in ice-cold assay buffer to a tissue concentration equivalent to 3.125 mg wet weight tissue / ml. All centrifugations were performed at 4°C. Membrane preparation buffer was 50 mM Tris-HCl (pH 7.7), 4 mM CaCl 2 and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris (pH 7.7), 4 mM CaCl 2 , 0.1% ascorbic acid and 10 μM pargyline.

[0619] For saturation binding analysis, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were diluted with 50 μl of 0.075–9.6 nM [ 3 H]8-OH-DPAT was incubated with either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (non-specific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0620] For the displacement assay, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μl of 0.6 nM [ 3H]8-OH-DPAT was incubated for 30 min at 25°C with either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (non-specific binding) or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10000 nM.

[0621] Membrane-bound radioactivity was harvested by filtration under vacuum through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. Filters were rapidly washed with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity was measured by liquid scintillation counting (1 ml Packard MV Gold scintillator).

[0622] The compound concentration required to inhibit 50% of the specific binding (IC 50 ) and Hill Slope were calculated by using nonlinear regression. i was calculated using a one-site binding model that takes into account ligand depletion.

[0623] Binding to 5-HT2A receptors in postmortem human frontal cortex Frontal cortices were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice and the pellet was homogenized again in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold 50 mM Tris-HCl assay buffer (pH 7.4, 1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was centrifuged twice more (20,500 x g, 10 min) to wash the tissue. The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer (pH 7.4) to a tissue concentration equivalent to 10 mg wet weight tissue / ml. All centrifugations were performed at 4°C.

[0624] For saturation binding analysis, frontal cortex membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were diluted with 50 μl of 0.00625–0.8 nM [ 3 H]MDL-100,907 was incubated with either 50 μl of assay buffer or 50 μl of 10 μM ketanserin (nonspecific binding) for 60 min at 25° C. Assay buffer and wash buffer consisted of 50 mM Tris-HCl buffer (pH 7.4).

[0625] For the displacement assay, frontal cortex membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were incubated for 60 min at 25°C with 50 μl of 0.1 nM [3H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (non-specific binding), or 50 μl of one of the test compounds at one of 10 concentrations ranging from 1 to 10,000 nM.

[0626] Membrane-bound radioactivity was collected and measured as above, and data analysis was also performed as above.

[0627] result In hippocampal membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.51, 0.28 and 0.52 nM, respectively.

[0628] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0629] In frontal cortical membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.11, 0.08 and 0.08 nM, respectively.

[0630] The mean inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0631] The selectivity ratios of psilocin, DMT and 5-MeO-DMT for the 5-HT2A receptor versus the 5-HT1A receptor were 0.78, 3.1 and 68, respectively.

[0632] Example 5 – Toxicity testing of 5-MeO-DMT 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101) under conditions that included treatment with concentrations up to 5000 μg / plate (the maximum recommended concentration according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

[0633] Example 6 – Pharmacokinetic evaluation of 5-MeO-DMT and bufotenine To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups (8 subjects per group) were formed. Subjects were administered a single dose of 6 mg, 12 mg, or 18 mg of 5-MeO-DMT by inhalation. Blood samples were collected at 1, 2, 4, 7, 10, 15, 20, 30, and 45 minutes and 1, 1.5, 2, 3, and 4 hours after administration.

[0634] 5-MeO-DMT concentrations were measured using LC-MS / MS. PK parameters were generated by algebraic analysis of individual concentration versus time plots. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0635] The median Cmax values ​​obtained in the three groups were 11.85 ng / ml (6 mg group), 22.90 ng / ml (12 mg group), and 38.45 ng / ml (18 mg group).

[0636] Table 1 below shows the median plasma concentration percentages of Cmax measured at the indicated time points. [Table 1]

[0637] Pharmacokinetic measurements were also performed using a dosing scheme based on ascending dose titration, with substantially similar results.

[0638] The plasma concentration of the 5-MeO-DMT metabolite bufotenine was also measured. In only a few samples were concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). From 15 min onwards, bufotenine concentrations were always below the LLOQ.

[0639] Substantially similar observations were made when subjects undergoing an escalating titration scheme were included.

[0640] Example 7 – Clinical Trial in Patients Affected by TRD A Phase 1 / 2 clinical trial of 5-MeO-DMT, administered by inhalation as described herein, has been completed in patients with treatment-resistant major depressive disorder (TRD). The study was designed in two parts. Part A was an open-label, single-arm, single-dose Phase 1 study with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B was an open-label, single-arm Phase 2 study applying an individualized dosing schedule with intrapatient escalating doses of 5-MeO-DMT. Patients (n=8) received at least one and up to three doses of 5-MeO-DMT daily (6 mg, 12 mg, and 18 mg), with higher doses administered only if the peak experience was not achieved with the previous dose. The primary endpoint of Part A was to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in patients with TRD. The primary endpoint of Part B was to evaluate the effect on depression severity, as measured by the proportion of patients in remission (defined as a MADRS total score of 10 or less) at 7 days after dosing.

[0641] In Part A, 3 of 4 patients in both arms (12 mg and 18 mg) experienced at least one ADR. All of them were mild and resolved spontaneously. No SAEs were reported.

[0642] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS resolution at post-dose day 7, and one additional patient (25%) in the 18 mg group had a MADRS clinical response at post-dose day 7. The mean MADRS change from baseline at day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0643] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0644] The primary endpoint was met, with 7 of 8 patients (87.5%) achieving MADRS remission at day 7 (p<0.0001). The mean MADRS change from baseline at day 7 was 24.4 (76%).

[0645] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or cognitive function measures in either Part A or Part B.

[0646] The results are summarized in the table below. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0647] Example 8 – Clinical trial of inhaled 5-MeO-DMT in patients with postpartum depression The single-arm, open-label clinical trial will enroll 15 adult female patients with a clinical diagnosis of postpartum depression (PPD).

[0648] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0649] More specifically, on day 0, patients will receive up to three doses of 5-MeO-DMT: 6 mg, 12 mg, and 18 mg.

[0650] 1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT. 2. The second dose (12 mg) is administered only if: a. Failure to achieve a peak experience (total score ≥ 75) after 6 mg administration; and b. If the 6 mg dose is deemed safe and well tolerated by the investigator, c. Any psychoactive effects (PsE) from the previous dose have subsided; and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or outside the normal ranges as determined by the investigator to be not clinically significant. 3. Similarly, the third dose (18 mg) is administered only if: a. Failure to achieve a peak experience (total score ≥ 75) after 12 mg administration; and b. The 12 mg dose is deemed safe and well tolerated by the investigator, and c. Any PsE from the previous dose has subsided; and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or outside the normal ranges as determined by the investigator to be not clinically significant.

[0651] Patients will be assessed post-injection for hallucinatory peak experiences (based on a patient-rated visual analog scale, the PE scale), sedation, and other endpoints. Follow-up visits will be scheduled 1 and 7 days after the date of injecting.

[0652] All patients considered for participation in a clinical trial must meet the following criteria: 1. Female and aged between 18 and 45 years (inclusive) at the time of screening. 2. Body mass index (BMI) at screening: 18.5-35 kg / m 2 The range is inclusive of the bounds. 3. Meets the PPD testing criteria as assessed by a testing psychiatrist or licensed psychologist: a. Diagnosis of major depressive disorder without psychotic features as confirmed by the Mini-Institutional Mental Health Interview (MINI) with perinatal onset occurring during pregnancy or later and within the first 4 weeks after delivery. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose on Day 0. 6. Must have discontinued breastfeeding at the time of screening, or if still breastfeeding or actively breastfeeding at screening, must agree to temporarily discontinue breastfeeding from just before study drug administration on Day 0 through 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24 hour period, but must incorporate expression / discarding at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding. 4. Must agree to maintain total abstinence (abstain completely from heterosexual intercourse) or use a highly effective (failure rate <1%) medically accepted method of contraception for 30 days prior to treatment and for 90 days after treatment with 5-MeO-DMT. Patients must have a negative pregnancy test at screening and the day before the study (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medication until the end of the study on Day 7 and agree to keep any psychotherapy unchanged during the study.

[0653] Potential patients meeting any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past diagnosis of bipolar disorder, manic or hypomanic episodes, psychotic disorder, major depressive disorder (MDD) or other mood disorder with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other comorbid psychiatric disorder that, in the opinion of the investigator, renders the patient unsuitable for the study. 2. Having one or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD). 3. At high risk for suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as determined by the clinical psychiatrist or licensed psychologist. 4. Receiving antidepressant therapy within 14 days or 5 half-lives (whichever is longer) prior to dosing (exception: within the past 5 weeks for fluoxetine). 5. Having received any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Have previously experienced a significant adverse reaction to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the study investigator. 7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindication. 8. Any current or past clinically significant medical condition that would cause the investigator to determine that the patient is unsuitable for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new-onset pregnancy-induced hypertension during pregnancy or the postnatal period (e.g., gestational hypertension, preeclampsia-eclampsia, aggravated preeclampsia), uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal insufficiency, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head trauma with loss of consciousness)). 9. The patient is receiving any medication or other substance that would cause the investigator to determine that the patient is unsuitable for the study. 10. Has clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that would cause the investigator to consider the patient unsuitable for the study. 11. Patient has a positive pregnancy test at screening or the day before the study (day -1), is pregnant, or intends to become pregnant during the study and up to 90 days after administration of 5-MeO-DMT. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0654] The primary objective of the study was to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0655] Secondary objectives are to determine the antidepressant and anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE), and effects on cognitive outcomes of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0656] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood and urine by LC / MS / MS measurement after daily IDR doses of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identity screening may be performed if necessary).

[0657] The primary endpoint of the study was the antidepressant effect of 5-MeO-DMT as measured by the percentage change from baseline in the MADRS at day 7.

[0658] Secondary endpoints included the antidepressant effects of 5-MeO-DMT assessed by: Antidepressant effects of 5-MeO-DMT assessed by: o Proportion of patients in remission (MADRS ≤ 10) at 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in MADRS assessed at 2 hours after the last dose of study drug on Day 0 and on Day 1; o Proportion of responders (≥ 50% reduction from baseline in MADRS total score) at 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; o Change from baseline in the Clinical Global Impression-Severity scale (CGI-S) at 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Effects on maternal behavior as assessed by percentage change from baseline to day 7 in the Barkin Index of Maternal Function (BIMF) total and subscale scores; Exposure to 5-MeO-DMT and bufotenin in breast milk obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, in the evening of day 0, and on days 1 and 7. Exposure to 5-MeO-DMT and bufotenin in blood obtained on the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, day 1, and day 7. Safety and tolerability of 5-MeO-DMT as assessed by: o reporting of treatment-emergent adverse events (TEAEs); o Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak expiratory flow measurements; o Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale (MOAA / S)) performed after each dose (when PsE subsided and 60 minutes after each study drug administration) and as part of the discharge evaluation on Day 0; o Change from baseline in the Clinician-Administered Dissociative Status Scale (CADSS), assessed as part of the discharge assessment on Day 0 and assessed on Days 1 and 7; o Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed as part of the discharge evaluation on Day 0 and assessed on Days 1 and 7; o Change from baseline in C-SSRS assessed as part of the discharge assessment on Day 0 and assessed on Days 1 and 7; o Change from baseline in YMRS assessed as part of the discharge assessment on Day 0 and assessed on Days 1 and 7; The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; o PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score ≥ 75); o Challenge Experience Questionnaire (CEQ); o Mystical Experiences Questionnaire (MEQ-30), Duration of PsE, defined as the time from administration of study drug to the point at which PsE subsided (as scored by the study physician and the patient) (ending 30–60 minutes after each dose).

[0659] So far, one patient with postpartum depression diagnosed by a psychiatrist has been enrolled in the clinical trial. The diagnosis was major depressive disorder without psychotic features, with perinatal onset occurring after conception and within the first 4 weeks after delivery, as confirmed by the Mini-Instrumental Mental Health Interview (MINI) (v7.0.2). The patient was diagnosed with postpartum depression after the birth of her third child. The patient completed all scheduled visits. The inhalation procedure was performed appropriately by the patient and was well tolerated, with no inhalation-related adverse events.

[0660] result Apart from a transient, clinically non-relevant increase in heart rate and blood pressure immediately following administration of 5-MeO-DMT, no other notable changes occurred in vital parameters. ECG (3 hours after administration) and safety laboratory analyses (day 7) and CADSS (3 hours, days 1 and 7) were also unremarkable. The few adverse events reported (crampy left abdominal pain and headache, both on day 0) were mild, short-lived, and resolved spontaneously by the end of the study.

[0661] Regarding the intensity of the hallucinatory experience, a PES score of 17.3 was achieved in response to exposure to the nominal 6 mg dose, indicating the need to proceed to a subsequent higher dose of 12 mg, as per the individualized dosing plan design. A PES score of 85.7 was achieved at this dose, ≥75, indicating that the patient experienced a hallucinatory peak experience and completed the IDR.

[0662] Importantly, this patient reported a significant improvement in depressive symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and this improvement was maintained over time (Table 4). This patient also met standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score ≤10). [Table 8-1] [Table 8-2]

[0663] In particular, significant improvements were noted on several MADRS items, which are outlined in Table 4. Patients' baseline scores reflected the absence of symptoms on some items (loss of appetite, difficulty concentrating, suicidal thoughts), whereas significant improvements were noted on items with scores reflecting severe symptoms (e.g., decreased sleep, inner tension).

[0664] Similarly, improvements were seen in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt, and tension.

[0665] Additionally, as outlined in Table 5, improvement in maternal function was evidenced by improvement in BIMF scores recorded on day 7, with the total score improving by 14%, from 92 to 105 (out of a maximum total of 120).

[0666] We also assessed several functional domains of maternal functioning, as defined by Barkin et al. Improvements in each functional domain are outlined in more detail in Table 6.

[0667] Here, notable improvements in self-care, psychological well-being, and management were achieved, with improvement rates ranging from 18% (management) to 44% (self-care). These improvements strengthen the relationship between improvement in depression items assessed by the MADRS and improvement in maternal functioning.

[0668] Note that the patient already had relatively high scores prior to treatment: in some areas of functioning, scores were at or near maximum values ​​(see Table 6), limiting the extent of improvement with treatment. [Table 9] [Table 10]

[0669] Summary and Conclusion A. An individualized dosing regimen of 6 mg inhaled 5-MeO-DMT followed by 12 mg inhaled 5-MeO-DMT was well tolerated and induced surprising and highly significant clinical responses in patients formally diagnosed with postpartum depression. B. Clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. Such rapid onset is unusual and not seen with traditional classes of antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others), which generally take 4-6 weeks to demonstrate efficacy. C. With IDR, patients experienced clinical remission within 2 hours of 5-MeO-DMT administration, which is vastly superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date. D. Significant clinical responses were maintained over the 7-day follow-up period even though 5-MeO-DMT was only administered once and was no longer effectively present in the body within the 7-day time frame (see pharmacokinetic data in Example 6 above). This observation supports the excellent clinical profile of 5-MeO-DMT and allows for convenient dosing intervals. E. In addition to the antidepressant effects, measures assessing other symptoms (e.g., hypochondriasis, emotional withdrawal, anxiety, guilt, and tension) were positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders. F. In addition to the antidepressant effects, outcomes assessing maternal functioning as assessed using the BIMF, such as self-care, psychological well-being, and control, were also positively affected. This supports further benefits of 5-MeO-DMT for patients suffering from PPD beyond improvement in core depressive symptoms.

[0670] The highlighted aspects show that when used in accordance with the present invention, 5-MeO-DMT has a significantly improved efficacy profile compared to approved pharmacological postpartum depression therapies and all previously tested hallucinogens.

[0671] These data, together with the short-term acute hallucinogenic effect and favorable safety profile, demonstrate that the present invention solves the technical problem of providing an improved psychoactive therapy for patients with postpartum depression.

[0672] Example 9 – Clinical trial of inhaled 5-MeO-DMT in patients with bipolar II disorder The single-arm, open-label clinical trial will enroll 15 adult patients with bipolar II disorder and a current major depressive episode.

[0673] Patients undergoing antidepressant therapy will need to discontinue such therapy or taper it over time.

[0674] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0675] More specifically, on the day of administration (day 0), patients will receive up to three doses of 5-MeO-DMT: 6 mg, 12 mg, and 18 mg.

[0676] 1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT. 2. The second dose (12 mg) is administered only if: a. Failure to achieve a peak experience (PES total score ≥ 75) after 6 mg administration; and b. If the 6 mg dose is safe and well tolerated, 3. Similarly, the third dose (18 mg) is administered only if: a. Failure to achieve a peak experience (PES total score ≥ 75) after 12 mg administration; and b. If the 12 mg dose is safe and well tolerated,

[0677] Patients will be assessed post-injection for hallucinogenic highs, sedation, and other endpoints based on the patient-scored PES. Follow-up visits are scheduled 1 and 7 days after the date of injecting.

[0678] Patient selection will be based on the following main inclusion criteria: 1. Understands the nature of the clinical trial and has provided signed and dated written informed consent, in accordance with local regulations, prior to any study-related activities. 2. Men or women aged 18-64 years (inclusive) at the time of screening. 3. Meets study criteria for bipolar II disorder and has experienced a major depressive episode as assessed by a study psychiatrist or licensed clinical psychologist: Meets the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for bipolar II disorder and has a current major depressive episode confirmed by the Mini-Institutional Interview for Mental Illnesses (MINI); b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 24 at screening and prior to the first dose on Day 0. 4. Young Mania Rating Scale (YMRS) total score ≤8 at screening and prior to the first dose on Day 0. 5. Agrees to keep any psychotherapy unchanged and not to start any new psychoactive drug therapy during the study. 6. Female patients must be surgically sterile (hysterectomy, tubal ligation, or bilateral oophorectomy (6 months prior to screening)) or postmenopausal amenorrhea for the last 2 years, or remain completely abstinent (total abstention from heterosexual intercourse) or use a highly effective (failure rate <1%) medically accepted method of contraception (including but not limited to bilateral tubal ligation / occlusion, hormonal contraceptives that suppress ovulation, intrauterine devices (including hormone-releasing intrauterine devices / systems)) for 30 days prior to and 90 days after 5-MeO-DMT treatment, and have a negative serum pregnancy test at screening and a negative urine pregnancy test the day prior to the study (day -1). 7. Male patients must use preventive contraception (i.e., condoms containing spermicide or abstinence) and must not donate sperm for 30 days after 5-MeO-DMT administration.

[0679] Potential patients meeting any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past diagnosis of bipolar I disorder, manic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorder with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other comorbid psychiatric disorder that, in the opinion of the investigator, renders the patient unsuitable for the study. 2. Have one or more first- or second-degree relatives currently or previously diagnosed with psychotic disorder, bipolar I disorder, or MDD with psychotic features. 3. Having significant suicide risk as defined by: (a) suicidal ideation within the past year, during the screening period, or at baseline, as supported by items 4 or 5 of the C-SSRS, or (b) suicidal behavior within the past year, or (c) a clinical assessment of significant suicide risk in a clinical interview, or (d) any nonsuicidal self-injury behavior within the past year. 4. Receiving antidepressant therapy within 7 days or 5 half-lives (whichever is longer) prior to dosing (exception: within the past 5 weeks for fluoxetine). 5. Having received medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Has received mood stabilizer therapy (e.g., lamotrigine, valproate, atypical antipsychotics) within 14 days (within 28 days for lithium) or within 5 half-lives (whichever is longer) prior to dosing, is receiving mood stabilizer therapy at screening, or is anticipated to require mood stabilizer therapy during the study (as determined by the investigator). 7. Have previously experienced a significant adverse reaction to a hallucinogenic or hallucinogenic drug, as determined by the study investigator. 8. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindication. 9. Any current or past clinically significant medical condition that may interfere with interpretation of the study results, pose a health risk to the patient, or otherwise cause the study investigator to determine that the patient is unsuitable for the study (e.g., severe infection, severe pulmonary disease, uncontrolled hypertension, uncontrolled diabetes mellitus, severe cardiovascular disease, severe liver or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head trauma with loss of consciousness)). 10. The patient is receiving any medication or other substance that, in the opinion of the study physician, makes the patient unsuitable for the study. 11. Has clinically significant abnormalities in physical examination, vital signs, electrocardiogram (ECG), or clinical laboratory parameters that would cause the study investigator to consider the patient unsuitable for the study. 12. Female patients with a positive pregnancy test at screening or the day prior to the study (Day -1) are pregnant, breastfeeding, or intend to become pregnant during the study or up to 30 days after administration of 5-MeO-DMT. 13. Patients have a DSM-5 alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

[0680] The primary objective of the study is to determine the onset and durability of antidepressant efficacy of daily individualized dosing schedules of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in patients with bipolar II disorder and a current major depressive episode.Secondary objectives are to determine the effects on depressive symptoms and global clinical status, safety and tolerability, intensity and duration of psychoactive effects (PsE), effects on sleep quality, and effects on cognitive outcomes of daily individualized dosing schedules of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in patients with bipolar II disorder and a current major depressive episode.

[0681] The primary endpoint of the study was the antidepressant effect of 5-MeO-DMT as measured by the percentage change from baseline in the MADRS at day 7.

[0682] Secondary endpoints included: Antidepressant effects of inhaled 5-MeO-DMT as assessed by: o Proportion of patients in remission (MADRS ≤ 10) at 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in MADRS assessed at 2 hours after the last dose of study drug on Day 0 and on Day 1; o Proportion of responders (≥ 50% reduction from baseline in MADRS total score) at 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in CGI-S at 2 hours after the last study drug dose on Day 0, and on Days 1 and 7; o Change from baseline in BDRS on days 1 and 7; Safety and tolerability of inhaled 5-MeO-DMT, as assessed by: o reporting of treatment-emergent adverse events (TEAEs); o clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and spirometry assessments; o Sedation assessment (Modified Observer Alertness / Sedation Scale [MOAA / S]) performed after each dose (when PsE subsided and 60 minutes after each study drug administration) and as part of the discharge evaluation on Day 0; o incidence of manic or hypomanic adverse events (AEs) (assessed using DSM-5 criteria for mania / hypomania); o Change from baseline in YMRS assessed as part of the discharge assessment on Day 0 and assessed on Days 1 and 7; o Change from baseline in the Clinician-Administered Dissociative Status Scale (CADSS), assessed as part of the discharge assessment on Day 0 and assessed on Days 1 and 7; o Assessment of patient readiness at discharge on day 0 using the Clinical Assessment of Discharge Readiness (CADR); o Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed as part of the discharge evaluation on Day 0 and assessed on Days 1 and 7; o C-SSRS classification based on the Columbia Classification Algorithm for Suicide Assessment (C-CASA); The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; o PsE assessment using the Peak Experience Scale (PES) to assess peak experience (PE) achievement (PES total score ≥ 75); o Challenge Experience Questionnaire (CEQ); o Mystical Experiences Questionnaire (MEQ-30), duration of PsE, defined as the time from administration of the study drug to the point at which PsE subsided (ending 30–60 min after each dose); - Effect on sleep quality, as measured by the percentage change in the Pittsburgh Sleep Quality Index (PSQI) from the day before the study (Day -1) to Days 1 and 7; Effect on cognitive outcomes, as assessed by percentage change from the day before the study (Day -1) to discharge on Day 0, Day 1, and Day 7 in: o Rapid Visual Processing (RVP) test, o Verbal Recognition Memory (VRM) test, o Spatial Working Memory (SWM) test, o Digit Symbol Substitution Test (DSST).

Claims

1. A pharmaceutical composition for the treatment of psychomotor retardation in a patient suffering from psychomotor retardation, comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein psychomotor retardation is reduced or eliminated by the aforementioned treatment.

3. The pharmaceutical composition according to claim 2, wherein the reduction or elimination of psychomotor retardation is observed about two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours, at least seven days, at least fourteen days, and / or at least twenty-eight days.

4. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from a mental disorder or nervous system disorder related to the psychomotor retardation.

5. The pharmaceutical composition according to claim 4, wherein the patient suffering from a mental disorder or neurological disorder is suffering from a treatment-resistant form of the said disorder.

6. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from a disorder characterized by depressive episodes associated with psychomotor retardation.

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

8. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from major depressive disorder (MDD) associated with the psychomotor retardation.

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

10. The pharmaceutical composition according to claim 4, wherein the treatment results in improvement of the disorder diagnosed in a patient who also suffers from related psychomotor retardation.

11. The pharmaceutical composition according to claim 10, wherein the improvement of the disorder diagnosed in a patient also suffering from associated psychomotor retardation, which is reflected in a reduction in the Clinical Global Impression-Severity (CGI-S) score, is observed approximately two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, approximately 24 hours, at least seven days, at least fourteen days, and / or at least twenty-eight days.

12. The pharmaceutical composition according to claim 1 or 2, wherein the patient suffers from a sleep disorder related to the psychomotor retardation.

13. The pharmaceutical composition according to claim 12, wherein the sleep disorder is insomnia related to the psychomotor retardation.

14. The pharmaceutical composition according to claim 12, wherein the patient suffers from an idiopathic sleep disorder related to the psychomotor retardation.

15. The pharmaceutical composition according to claim 12, wherein the patient is suffering from a treatment-resistant form of the disorder.

16. The pharmaceutical composition according to claim 12, wherein the sleep disorder occurs in a patient who also suffers from associated psychomotor retardation and a mental or neurological disorder, such as a disorder characterized by a depressive episode, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, a mental and behavioral disorder resulting from psychoactive substance use, such as substance use disorder (SUD), a psychotic disorder, such as schizophrenia, a dementia, such as Alzheimer's disease (AD), Lewy body dementia (DLB), vascular dementia, and Parkinson's disease dementia, Parkinson's disease (PD), and chronic fatigue syndrome.

17. The pharmaceutical composition according to claim 16, wherein the treatment brings about improvement in psychomotor retardation and sleep disorders, and further brings about improvement in related mental disorders or nervous system disorders.

18. The pharmaceutical composition according to claim 15, wherein the treatment results in improvement of the sleep disorder.

19. The pharmaceutical composition according to claim 18, wherein the improvement in the sleep disorder, reflected in a reduction in the Clinical Global Impression-Severity (CGI-S) score, is observed at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours later, at least seven days later, at least fourteen days later, and / or at least twenty-eight days later.

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

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

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

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

24. The pharmaceutical composition according to claim 23, wherein each subsequent dose is administered in a larger amount than the previous dose.

25. The pharmaceutical composition according to claim 23, wherein the patient receives a subsequent dose unless the patient experiences a hallucinogenic peak experience.

26. The pharmaceutical composition according to claim 1 or 2, wherein 5-MeO-DMT is administered in a dose of approximately 2 mg to approximately 8 mg for a first dose, and thereafter, unless the patient has not yet experienced a peak hallucinogenic experience or the attending physician determines that further dose increases are inappropriate based on observed side effects, the dose is increased to approximately 8 mg to approximately 14 mg for a second dose, and thereafter, unless the patient has not yet experienced a peak hallucinogenic experience or the attending physician determines that further dose increases are inappropriate based on observed side effects, the dose is increased to approximately 14 mg to approximately 20 mg for a third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered.

27. The pharmaceutical composition according to claim 26, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered.

28. The pharmaceutical composition according to claim 23, wherein the interval between two administrations is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably 1 to 2 hours.

29. The pharmaceutical composition according to claim 20, wherein the occurrence of a peak hallucinatory experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales of the Revised 30-Item Mystical Experiences Questionnaire (MEQ30) (mystical, positive mood, transcendence of time and space, and inexpressibility), or by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) aspect of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 75 in the total Peak Experience Scale (PES) score.

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

31. The pharmaceutical composition according to claim 1 or 2, wherein the psychomotor retardation is measured by the Salpêtrière retardation rating scale (SRRS).