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, and 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous routes.

Description

[Technical field]

[0001] The present invention relates to improved methods for the treatment of psychomotor retardation in patients suffering from psychiatric or nervous system disorders, for example disorders characterised 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 behavioural disorders resulting from the use of psychoactive substances, 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 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 a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof to a patient in need thereof. [Background technology]

[0004] Psychomotor retardation is characterized by reduced energy and activity, as well as reduced motivation. Psychomotor retardation involves a slowing of thinking and reduced physical movement in an individual. Psychomotor dysfunction 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 (i.e., a) a greater percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a more rapid onset of clinical response, and / or d) a more durable clinical response) than the above-mentioned therapies.

[0007] It is a further object of the present invention to provide compounds for improved psychoactive therapy and dosage regimens for said therapy that have a better safety profile and / or are better tolerated than the above-mentioned therapies. Another object of the present invention is to provide compounds for improved psychoactive therapy and dosage regimens for said therapy that are more convenient than the previously described therapies. Another object of the present invention is to provide compounds for improved psychoactive therapy and dosage regimens for said therapy that are associated with higher patient compliance (including higher treatment initiation rates) than the previously described therapies. A still further object of the present invention is to identify specific disease conditions and specific disease subgroups 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 the use of psychoactive substances, 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 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.

[0012] In the context of the present invention, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, is administered via intravenous, intramuscular, or subcutaneous administration.

[0013] The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered at a dose or regimen that induces the patient to experience a psychedelic peak experience. A dose of about 1 mg to about 10 mg of 5-MeO-DMT, or an equimolar amount of a pharma- ceutically acceptable salt, may be administered. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition When used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is contemplated that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated from the weight of the free base, assuming that an equimolar amount is used.

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

[0016] The diagnosis of mental or nervous system disorders may be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will be evident from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or groups of patients who will particularly benefit from the treatment according to the invention. The diagnosis is in any case made by a physician or psychologist. It is not sufficient that the human subject himself considers himself to be suffering from the disorder in question.

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

[0018] "Treatment of psychomotor retardation" is intended to include the management and care of a patient for the purpose of addressing psychomotor retardation and includes the administration of compounds and methods according to the invention to alleviate the signs and / or symptoms of psychomotor retardation or to eliminate psychomotor retardation.

[0019] The psychomotor retardation may be associated with a sleep disorder, eg, insomnia, a psychiatric or nervous system disorder, or another medical condition.

[0020] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two adequate treatment courses. In particular, the patient has not shown sufficient improvement 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 shown sufficient improvement after at least two adequate drug therapy courses. At least two past treatment courses are specifically administered during the ongoing disease episode, for example, when the patient suffers from a disorder characterized by depressive episodes in the ongoing depressive episode.

[0021] 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.

[0022] "Clinical response" includes, but is not limited to, improvements on rating scales that assess: (i) psychomotor retardation or aspects of psychomotor retardation, and / or (ii) psychiatric or nervous system disorders or aspects of such disorders, and / or (iii) sleep.

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

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

[0025] 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 your 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.

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

[0027] A 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 that the CGI-S score decreases by at least one step. Preferably, the CGI-S score decreases by at least two steps and / or the score reaches 0. Particularly preferred is a decrease in the CGI-S score of at least three steps and / or the score reaches 0.

[0028] Alternatively, the success of treatment can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, just one question is rated on a 7-point scale: "Compared to the patient's condition at the time of entry into the project (before medication was started), this patient's condition has improved: 1 = very much since starting treatment, 2 = much, 3 = minimally, 4 = unchanged from baseline (at the start of treatment), 5 = minimally, 6 = much, 7 = very much worse since starting treatment."

[0029] 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).

[0030] In addition to the individual items of the scales described herein, sub-combinations of the individual items may be used to assess specific disease aspects.

[0031] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a possible amount of an active compound or pharmaceutical ingredient into a patient by any route. The active compound may be administered by intravenous, intramuscular or subcutaneous administration.

[0032] 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.

[0033] Psychomotor retardation The main aspects observed in patients suffering from psychomotor retardation are reduced energy and activity, as well as reduced motivation.

[0034] Psychomotor retardation involves a slowing of thinking and a decrease in physical movements in an individual. Psychomotor impairment can cause a noticeable slowing of physical and emotional responses.

[0035] The psychomotor retardation may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0036] Mental or nervous system disorders resulting in or associated with psychomotor retardation include 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 the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; chronic fatigue syndrome.

[0037] Psychomotor retardation can also occur in patients suffering from sleep disorders, such as insomnia.

[0038] 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), and others known in the art.

[0039] For example, in the Trail Making Test (TMT), subjects must connect 25 circles containing either numbers (TMT A) or combinations of numbers and letters (TMT B) in ascending order. The requirements of the task are similar to those of TMT-B, but 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 taken to complete the task.

[0040] Another test of graphomotor ability is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not influenced by cognitive ability: subjects completing the GSM must accurately traverse a spiral maze from start to finish without touching the borders.

[0041] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of number-symbol pairs followed by a list of numbers. Under each number, the subject must write the corresponding symbol as quickly as possible. The score is the number of symbols correctly reported in 90 seconds. A further example of a motor test is the finger tapping test.

[0042] Thus, certain tests combine measures of both the motor and cognitive aspects of psychomotor retardation, while still other tests assess only the motor aspects.

[0043] Speech analysis can be a further indicator of psychomotor retardation.

[0044] The main scales available for assessment and measurement include severity of psychomotor retardation, the Salpetriere Retardation Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

[0045] The Salpêtrière Retardation Rating Scale (SRRS), developed by Widlocher, assesses cognitive and motor aspects through 15 items. The first three measure movements, specifically the quality of walking, and slowness of limb, trunk, head, and neck movements. The next three items focus on speech, including speech flow, tone of voice, and length of response. Two items are designed to objectively measure cognitive function. These questions are based on interview conversations and measure the patient's ability to engage with and develop 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 symptoms presented, with a total score ranging from 0 to 60.

[0046] The Motor Agitation and Retardation Scale (MARS) assesses only motor aspects. It was designed to assess psychomotor impairments in depressive disorders. Psychomotor impairments are divided into five major somatic categories including eyes, face, voice, limbs, and trunk, with a total of 19 scale items. Items in the eyes category include direction of gaze, blink amount, gaze, and eye movement. Items associated with the face category include facial expression and facial expressiveness. The voice category has items including volume, slurring, tone, and onset time. Items under the limbs category include hand, foot, and leg movements, gait, slowness of movement, and hand tension. Items under 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. Nine of the 19 items relate to motor agitation, and ten items assess motor retardation. Delay items include abnormal gait, trunk / proximal limb immobility, postural collapse, bradykinesia (i.e., limb and trunk categories), lack of facial expressiveness, downcast eyes (i.e., eye and face categories), and reduced vocal volume, slurred speech, delayed speech onset, monotonous speech (i.e., voice category). The MARS scale provides a rapid clinical assessment of motor signs.

[0047] Scales for assessing psychiatric and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders and are based on tests that can be self-administered or administered by a clinician.

[0048] Measures that may be used in accordance with the present invention include those known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0049] Treatment outcome is assessed using one or more indexes or measures at one or more time points after completion of the course of treatment.

[0050] The assessment may be performed after the acute hallucinatory experience has subsided. A suitable time point for early assessment is generally about 2-3 hours after the last dose. Early assessments may generally be performed, for example, about 2 hours or about 3 hours after the last dose.

[0051] However, assessment of the effect on sleep disorders can be performed no earlier than the day after treatment (ie, day 1), so that treated patients have had the opportunity to get at least a full night's sleep.

[0052] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. Evaluation is performed no earlier than 12 hours after the last dose, and in any case no earlier than one night after the last dose and no later than 36 hours after the last dose. Evaluation may be performed after about 24 hours.

[0053] 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.

[0054] If the clinical response is evaluated at an early time point (e.g., 2 hours) after drug administration, based on an endpoint that is established with a longer recall period (e.g., typically 7 days for MADRS), for example, using one of the scales for evaluating the severity of psychiatric or nervous system disorders, such endpoints can be reasonably modified (e.g., changing the recall period of MADRS to 2 hours, and carrying forward the sleep items recorded at baseline before drug administration). The same applies to any other scales applied herein, unless recall period is specifically indicated.

[0055] At early time points the considerations outlined apply because, on the one hand, the influence of the patient's state 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, sleep items cannot be assessed 2 hours after administration of the drug.

[0056] At later time points (e.g., after day 1), all items of the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that there is no need to carry forward any pre-treatment scores.

[0057] Resting-state networks and psychomotor retardation Brain processing can be investigated 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.

[0058] Functional brain images are acquired over a period of several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anti-correlated fluctuations.

[0059] Thus, 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 in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterizing networks of brain regions with coherent patterns of signal changes are called resting-state networks (RSNs).

[0060] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in working fMRI experiments.

[0061] Resting-state fMRI can therefore 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.

[0062] RSNs have been shown to mediate 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 within a particular resting-state network and / or between one or more regions within one or more additional resting-state networks.

[0063] For example, abnormalities in functional connectivity from the somatosensory motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks have been reported, which correlated with both psychomotor retardation and agitation in depressive disorders.

[0064] In many cases, the resting-state network involved in psychomotor retardation is affected by psychiatric or neurological 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 the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; chronic fatigue syndrome.

[0065] Resting-state networks involved in psychomotor retardation are also affected by sleep disorders, such as insomnia, and indeed psychomotor retardation and sleep dysfunction are correlated.

[0066] Treatment of psychomotor retardation and mental or nervous system disorders According to the present invention, psychomotor retardation in patients suffering from psychiatric or nervous system disorders can be treated. Additionally, psychomotor retardation occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0067] In patients suffering from psychomotor retardation associated with another condition detailed above, treatment of the psychomotor retardation according to the invention results in amelioration of the condition associated with the psychomotor retardation.

[0068] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0069] 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 pathological poorly connected connections as the networks reconnect. New healthy functional connections are established, with lasting effects.

[0070] Thus, in accordance with the present invention, affecting these resting state networks by the therapies described herein improves psychomotor retardation, improves a psychiatric or nervous system disorder if the treated patient suffers from such a disorder, and improves a sleep disorder, e.g., insomnia, if the treated patient suffers from such a disorder.

[0071] 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 reasons, noting the specific improvement of psychomotor retardation that is also commonly observed in patients with other disorders.

[0072] This data is derived 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 medical condition, as detailed below, the inventors have determined that certain clinical findings obtained in the study are relevant to devising treatments for other medical conditions associated with psychomotor retardation.

[0073] In the clinical trial, 5-MeO-DMT was administered by inhalation (as 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 the group that received a single dose of 12 mg and the group that received an individualized daily dosing schedule (IDR) that allowed multiple ascending doses within a day (6 mg, 12 mg and 18 mg) determined by the intensity of the patient-reported hallucinatory experience.

[0074] The collected data includes the evaluation of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). Although the focus of this study was to demonstrate the effect of treatment through the improvement of the overall MADRS score, the inventors focused on the eyes including various assessment scales, and realized that items related to psychomotor retardation as well as items of specific subscores are also related to other pathologies based on similarly altered functional connectivity within and / or between somatomotor / sensorimotor networks, visual networks, dorsal attention networks, and default mode networks.

[0075] Multiple patients within the pooled cohort showed significant improvement, the results supporting our findings that 5-MeO-DMT is a suitable compound for the treatment of patients with these conditions.

[0076] More specifically, an aspect that may be treated by administration of 5-MeO-DMT is psychomotor retardation, which, when administered to a patient, can reduce or eliminate the patient's psychomotor retardation.

[0077] A MADRS scale item that is particularly relevant to psychomotor retardation is "apathy," which describes difficulty getting started or slowness in initiating and carrying out everyday activities.

[0078] A score of 0 means there is little difficulty in getting started and no sluggishness. If the patient has difficulty initiating activities, a score of 2 is assigned. A score of 4 means simple daily activities are difficult to initiate and require effort to perform. A score of 6 is assigned if there is complete lethargy and the patient is unable to do anything without assistance.

[0079] The combined MADRS item "apathy" score for all eight patients in the study group receiving the individualized dosing regimen was 27 at baseline.

[0080] After 2 hours, the score decreased to 10, which corresponds to a 17-point or 63% improvement. On the first day after treatment, the score decreased to 5, which corresponds to a 22-point or 81% improvement. On the seventh day after treatment, the score decreased to 3, which corresponds to a 24-point or 89% improvement.

[0081] In the 12 mg group, the combined MADRS "apathy" score for all four patients had a baseline of 16. After 2 hours, the score had decreased to 10, corresponding to a 6-point or 38% improvement. One day after treatment, the score had decreased to 0, corresponding to a 16-point or 100% improvement. Seven days after treatment, the score had decreased to 3, corresponding to a 13-point or 81% improvement.

[0082] Thus, the score for the scale item "apathy", which is particularly relevant to psychomotor retardation, is significantly improved. The inventors conclude that 5-MeO-DMT may 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.

[0083] 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.

[0084] Activator The above discussion indicates that psychomotor retardation itself poses a significant disease burden and deserves appropriate treatment.

[0085] The inventors believed that a carefully selected hallucinogen could improve the treatment of important aspects of psychomotor retardation and improve the condition overall.

[0086] One group of hallucinogens involves compounds that bind to the 5-hydroxytryptamine (5-HT) receptors (seven families are described, 5-HT1 to 5-HT7, with several subtypes), also called serotonin receptors. Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often called "hallucinogens" and highlight their primary ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), but with minimal other effects such as sedation, narcosis, or hyperstimulation.

[0087] Chemically, serotonergic hallucinogens are either phenylalkylamines or indolamines, the indolamines being divided into two subsets, the ergolines and tryptamines, the latter being derived from tryptamine.

[0088] Serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (especially 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets (e.g., monoamine transporters and trace amine-associated receptors).

[0089] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may be alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may preclude their clinical use.

[0090] 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 had a manic episode after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that subsided, but about 3 weeks later a typical manic episode of psychotic level occurred. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a self-reported manic episode after ingesting psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ingestion of ayahuasca, a DMT-containing preparation, in a man with bipolar disorder.

[0091] 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.

[0092] 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 needs to be appropriately selected and is preferably administered in a specific dosing regimen.

[0093] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a unique pharmacological profile that differs from the pharmacological profiles of other hallucinogenic compounds.

[0094] 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.

[0095] As described in further detail in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin that is formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brains were i The inhibition constants (K values) of psilocin, DMT and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains are 48, 38 and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity, whereas psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe affinity (p < 0.05) for the 5-HT2A receptor is 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.

[0096] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has enhanced affinity for the 5-HT1A receptor and acts as a strong agonist. In the case of psilocin and DMT, the contribution to 5-HT2A binding is higher compared to 5-MeO-DMT, and the latter has the largest difference between its affinity for 5-HT1A and 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role than 5-HT2A binding in the overall effect of 5-MeO-DMT compared to the other two compounds.

[0097] It has been reported that 5-HT1A receptor agonism reduces impulsivity and aggression, whereas 5-HT2A receptor agonism may increase these same traits in the short term. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activation resulting in mania. LSD, psilocybin, and DMT all have greater affinity for various dopamine receptors compared to 5-MeO-DMT.

[0098] Compared to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT can be administered, preferably using the administration schemes described herein, to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes, 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, when treated according to the present invention, do not experience treatment-emerged mania or hypomania.

[0099] 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.

[0100] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering an excessive dose, which may be accompanied by adverse events.

[0101] 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.

[0102] 5-MeO-DMT can induce peak experiences, experiences characterized by an emotional perspective shift described as a "loss of self", which often result in an overwhelming feeling of "oneness with the universe" more rapidly than other hallucinogens, and with a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile that can be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0103] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for this receptor. 3H]LSD, and serotonin were used to estimate nonspecific binding, and K i was determined to be 2.3 nM.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, especially those involving sleep disorders. Resting-state functional connectivity analysis in patients suffering from sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0108] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe that this will allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0109] 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 pharmacological efficacy of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0110] 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 of 5-MeO-DMT, including the "resetting" of the functional connectivity of the network and the neuroplasticity effects, allows for a beneficial effect in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, negative thinking, sleep disorders, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0111] Another characteristic of 5-MeO-DMT is its short half-life.

[0112] 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.

[0113] 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.

[0114] 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 with 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.

[0115] The properties of 5-MeO-DMT make the compound particularly suitable for the treatment of psychomotor retardation, especially for patients suffering from psychiatric or nervous system disorders.

[0116] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0117] In accordance with the present invention, isotopic variants of 5-MeO-DMT and pharma- ceutically acceptable salts thereof may also be used. Where reference is made to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0118] Such variants are in particular deuterated forms of 5-MeO-DMT and pharma- ceutically acceptable salts of such forms.

[0119] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than would be expected based on the natural abundance of this isotope.

[0120] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced at one or more defined hydrogen positions.

[0121] 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.

[0122] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Even more examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It should be noted that combinations of the above substitution patterns are also contemplated.

[0123] Methods for preparing these compounds are known in the art.

[0124] 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.

[0125] 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.

[0126] 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 with a 5-MeO-DMT prodrug or a salt thereof.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] Prodrugs, especially those of the above structure, can also be used in the form of pharma- ceutically acceptable salts.

[0131] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitrifluoroacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0132] Methods for preparing the prodrugs described herein are known in the art.

[0133] 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, especially 0.5 hours or less.

[0134] 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.

[0135] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., by intravenous injection.

[0136] 5-MeO-DMT can be used as a pharma- ceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection, examples of excipients and vehicles for such formulations are known in the art.

[0137] Dosage regimen The present invention also provides dose ranges, specific doses, as well as dosing regimens (administration schemes) and suitable routes of administration.

[0138] The present invention is based in part on the inventors' conclusion that the occurrence of a peak hallucinatory experience in the acute phase following administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof causally promotes, or at least as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from psychomotor retardation, in particular one or more of the aspects defined above.

[0139] Thus, achieving a peak experience more quickly, in a greater percentage of patients, and with greater reproducibility within an individual patient compared to previously tested hallucinogens, dosing regimens, and routes of administration would result in a superior therapeutic profile.

[0140] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the associated lack of 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 climax 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 treatment approach and improve overall compliance at the patient population level.

[0141] 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, as well as the rapid development of tolerance (i.e., the hallucinogenic effect diminishes or disappears after re-administration), which may last for several days.

[0142] Patients, as defined herein, suffering from psychomotor retardation are treated by administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0143] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for psychomotor retardation).

[0144] The dosage of 5-MeO-DMT administered to a patient suffering from psychomotor retardation, as defined herein, ranges from about 1 mg to about 10 mg, or any amount within this range, administered in the form of an administration formulation based on a pharma- ceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated from the stated weight of 5-MeO-DMT free base, assuming that an equimolar amount is used. Effective specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. It should be noted that when a range is given herein, such as "about 1 mg to about 10 mg," the inventors contemplate all discrete values ​​within the range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0145] In a preferred embodiment, the improved method for treating a patient suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT as defined herein comprises a clinical response occurring within about 2 hours of administration of 5-MeO-DMT.

[0146] In a preferred embodiment, the improved method for treating a patient suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT as defined herein comprises a clinical response that occurs within about 2 hours of administration of 5-MeO-DMT and that lasts for at least about 6 days after the last administration of 5-MeO-DMT, preferably at least about 14 days after the last administration of 5-MeO-DMT, and more preferably at least about 28 days after the last administration of 5-MeO-DMT.

[0147] In a preferred embodiment, the improved method for treating a patient suffering from psychomotor retardation with a therapeutically effective amount of 5-MeO-DMT as defined herein comprises administering more than one dose of 5-MeO-DMT.

[0148] In a preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2-7 treatments, with the interval between each treatment within each treatment block being greater than or equal to about 1 hour and less than or equal to about 24 hours, and with 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.

[0149] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0150] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1-3 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.

[0151] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0152] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0153] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a peak hallucinatory experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0154] In embodiments where the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage of the previous administration. For example, if the dosage of the first administration is 1 mg and the dosage increase is 3 mg, the dosage of the second administration will be 4 mg unless one of the previously mentioned stopping criteria is reached. Preferably, the dosage of the third administration will be 7 mg.

[0155] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first treatment, and then increased to a dosage selected from about 4 mg to about 6 mg for the second treatment, and to a dosage selected from about 7 mg to about 9 mg for the third treatment, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third treatments are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0156] In additional preferred embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first treatment, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second treatment, and to a dosage selected from about 2.5 mg to about 3.5 mg for the third treatment, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third treatments are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0157] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration in a first treatment block, and then increased for each subsequent administration in the first treatment block until it reaches 10 mg or all administrations in that treatment block have been administered, whichever occurs first, or until the patient experiences a peak hallucinatory 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 in those subsequent treatment blocks. For example, if the highest dosage in the first treatment block is 8 mg because the patient experienced a peak hallucinatory experience at a dose of 8 mg, then the dosage for all subsequent treatment blocks and administrations in those subsequent treatment blocks will be 8 mg.

[0158] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration in the first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration in the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration in the first treatment block, unless the patient has yet to experience a peak hallucinogenic experience 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 effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0159] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of the first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a peak hallucinogenic experience 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 effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0160] Pharmaceutically acceptable salts of 5-MeO-DMT are preferably used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming that an equimolar amount is used.

[0161] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0162] The occurrence of a "peak hallucinatory 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).

[0163] The occurrence of a "peak hallucinatory 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).

[0164] In accordance with the present invention, the occurrence of a "peak hallucinatory experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, scored on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control did it make you feel? 3. How profound (i.e., meaningful) was the experience?

[0165] Treatment of psychomotor retardation and sleep disorders A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder, that affects a person's ability to function adequately during wakefulness and is associated with a pattern of high negative affect and low positive affect.

[0166] 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 alternates with REM sleep during each of the four to five cycles of normal human sleep each night. Early in the night, non-REM sleep is deeper and occupies a disproportionate amount of time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower and more of each cycle is allocated to REM sleep.

[0167] Normal healthy sleep consists of different stages, as outlined above, which proceed sequentially and in a strictly controlled sequence throughout the night.

[0168] When this tight control is disrupted, sleep disorders result.

[0169] Common forms of sleep disorders include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders). In a broader sense, fatigue can also be considered a sleep disorder.

[0170] Insomnia is a sleep disorder that makes it difficult for people to fall asleep or stay asleep. People with insomnia have difficulty falling asleep, frequent awakenings during the night and difficulty returning to sleep, excessive early morning awakenings, unrefreshing sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, concentration problems, accidents at work or while driving.

[0171] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. This is a difficulty in transitioning from sleep to wakefulness. Individuals who experience sleep drunkenness report confusion, disorientation, sluggishness upon awakening, and repeated returns to sleep.

[0172] Circadian rhythm disorders are characterized by chronic or recurrent sleep disorders resulting from alterations in an individual's internal circadian rhythm or from a mismatch between that circadian rhythm and desired or necessary work or social schedules. This desynchronization may be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and interrupted, performance during desired wakefulness is impaired, and temporary opportunities to return to a normal sleep schedule are unsuccessful.

[0173] Parasomnia refers to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) that people experience before falling asleep, during sleep, or during periods of arousal between sleep and wakefulness. Considerable variation exists with regard to characteristics, severity, and frequency. Parasomnia may impair sleep quality.

[0174] Sleep-related breathing disorders are characterized by abnormal 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, which can have a profound effect on sleep and the balance of oxygen and carbon dioxide in the blood, are manifested as chronic snoring, sleep apnea, sleep-related hypoventilation and / or hypoxemia. In some of these disorders, breathing is abnormal even during wakefulness. Reduced airflow leads to intermittent hypoxia with micro-awakenings or awakenings, causing sleep fragmentation and excessive daytime sleepiness. Inflammation and endothelial dysfunction can result in reduced vascular elasticity and increased blood clotting, predisposing individuals to atherosclerosis, which, in conjunction with reduced oxygen supply, can cause heart and brain damage.

[0175] In sleep-related movement disorders, movements that are repetitive, relatively simple, and usually stereotyped, interfere with sleep or the onset of sleep, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0176] Fatigue describes a state of tiredness that is not resolved by rest or sleep. It is a feeling of exhaustion, weariness, or reduced energy, usually experienced as a weakening or depletion of a person's physical or mental resources, and is characterized by a decreased capacity to work and a decreased efficiency of responding to stimuli. Mental or physical fatigue is normal after a period of strenuous activity, but may also occur in the absence of such activity as a symptom of a health condition.

[0177] Not getting adequate amount or quality of sleep can lead to personality changes and may not only exacerbate existing psychiatric disorders but may also precipitate the onset of new psychiatric disorders.

[0178] 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 cardiovascular disease.

[0179] Treatment of sleep disorders varies depending on their type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered primary treatments. If unsuccessful, treatment may also involve medication or psychotherapy.

[0180] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve the relevant therapeutic effect.

[0181] 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 always improve the sleep disorder.

[0182] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treating depression does not necessarily result in improvement of the concomitant sleep disorders. Most antidepressants have been shown to affect sleep architecture, but while some classes of antidepressants improve sleep, 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).

[0183] To assess sleep, parameters such as sleep time, sleep architecture, sleep latency, and frequency and duration of awakenings throughout the night can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-reported measures (questionnaires).

[0184] Polysomnography is a technique that requires the patient to be monitored overnight in a specialized clinic, where various functions such as eye movement, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body position and movement, snoring, and heart rate are measured throughout the night.

[0185] 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 across a range of test naps. A mean sleep latency of about 10 minutes is considered normal, while less than 8 minutes suggests a sleep disorder. Analysis of the associated brain activity can aid in further diagnosis of sleep disorders.

[0186] The sleep assessment questionnaire obtains assessment of components of sleep quality such as perception of depth of sleep, difficulty waking, and feeling of restlessness after sleep, in addition to other factors that may affect sleep quality such as comorbidities and medication use.

[0187] Assessment of qualitative aspects of the sleep experience is important because sleep complaints often persist even when quantitative measures of sleep are normal.

[0188] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful for tracking patient progress. Therefore, self-reported sleep questionnaires completed by patients are an important pillar of the assessment of sleep disorders in clinical practice.

[0189] Various sleep quality indices are known. The following indices each include examples of questionnaires for assessing sleep in general, and for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnia behaviors in particular. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0190] Sleep quality can generally be assessed, for example, with the Sleep Quality Scale (SQS) and the Sleep-50 questionnaire.

[0191] The Sleep Quality Scale (SQS) is a comprehensive assessment tool to achieve a general and efficient measurement suitable for assessing sleep quality in various patient and research populations. Individual questions regarding symptoms such as attention, concentration difficulties, or memory problems (item 15, "I have difficulty thinking because of lack of sleep," item 19, "I make mistakes at work because of lack of sleep," item 21, "I forget things because of lack of sleep," item 22, "I have difficulty concentrating on work because of lack of sleep"), recovery after sleep, problems initiating and maintaining sleep, difficulty waking, and satisfaction with sleep can be scored from 0 ("almost never") to 3 ("almost always"), with higher scores indicating more acute sleep problems.

[0192] 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, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep complaints on daily functioning, as well as factors required for diagnosis. For each item, respondents are given a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate how well the statement matched their own experience over the previous month or another suitable recall period.

[0193] To diagnose a sleep disorder, the questionnaire requires that not only certain subscales (e.g., insomnia) but also the impact subscale exceed certain cut-off points (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46, see Table 4 for optimal cut-offs and scoring procedure).

[0194] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0195] A common questionnaire to assess sleep disorders is the Pittsburgh Sleep Quality Index. Other instruments are the Insomnia Severity Index and the Espie Sleep Disorders Questionnaire.

[0196] 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.

[0197] 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.

[0198] Each component is assigned a score from 0 to 3. Higher scores indicate more acute sleep disturbance. Details of how the Pittsburgh Sleep Quality Index is scored 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.

[0199] 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.

[0200] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease of 5 or less.

[0201] The Insomnia Severity Inventory (ISI) is a five-item questionnaire that assesses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning (item 3 “How much do you think your sleep problems interfere with daily functioning” (e.g., daytime fatigue, ability to complete tasks / chores, concentration, memory, mood, etc.), how significant the respondent feels their insomnia is 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). Higher total scores correspond to more severe insomnia. A total score of 0–7 indicates “no clinically significant insomnia”, 8–14 means “subthreshold insomnia”, 15–21 means “clinical insomnia (moderate severity)”, and 22–28 means “clinical insomnia (severe)” (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012;Bastien et al.Validation of the Insomnia Severity Index as an outcome measure for insomnia research.Sleep Med.2001 Jul;2(4):297-307).

[0202] The typical recall period for the ISI is two weeks, although other suitable recall periods may be used herein.

[0203] Successful treatment is indicated in cases of clinically significant insomnia by (i) a reduction in score of, for example, >7 points, particularly >8 points, and preferably (ii) a reduction below the cut-off score.

[0204] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. With scores on restlessness / irritability, mental overactivity, consequences of insomnia, and lack of readiness to fall asleep, the SDQ is particularly relevant to beliefs about the causes of sleep disturbance. Respondents indicate how frequently a particular statement about insomnia describes their experience using a 5-point scale, with 1 meaning "not true at all" and 5 meaning "true most of the time." Higher scores indicate more dysfunctional 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).

[0205] Successful treatment is indicated by a decrease in score.

[0206] Hypersomnia or hypersomnolence may be assessed by the Epworth Sleepiness Scale, the Stanfold Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0207] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. In the questionnaire, respondents are asked to rate how likely they are to fall asleep in eight different situations that represent moments of relative inactivity, such as an afternoon nap or while sitting in a car stopped in traffic. Using a scale of 0 to 3 (0 meaning "will never fall asleep" and 3 meaning "will likely fall asleep"), respondents rate their own likelihood of falling asleep. Scoring ranges from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (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).

[0208] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0209] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a particular moment. This single-item scale asks respondents to select one of seven statements that best describes their current perceived level of sleepiness. Levels of sleepiness are assessed using a scale ranging from 1 (= active, energetic mood, alert, fully awake) to 7 (= almost dreamy, close to falling asleep, losing effort to stay awake) (A. Shahid et al., loc.cit.; Hoddes et al. The development and use of the Stanford sleepiness scale (SSS). Psychophysiology, 1972, 9, 150).

[0210] Successful treatment is indicated by a decrease in score.

[0211] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0212] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists abnormal sleep behaviors, assesses their frequency, and also includes an assessment of their consequence (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0213] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0214] 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.

[0215] Successful treatment is indicated by a decrease in score.

[0216] 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).

[0217] Treatment response can be assessed by a reduction in score.

[0218] Fatigue is commonly assessed, for example, by the FACES (Fatigue, Anergy, Consciousness, Energy, Sleepiness) instrument.

[0219] The FACES (Fatigue, Anergy, Consciousness, Energy, Sleepiness) scale is a 50-item checklist to distinguish between tiredness, sleepiness, and fatigue. Respondents indicate the degree to which they have experienced each emotion or energy state during the previous week or another suitable recall period using a scale ranging from 0 ("not at all") to 3 ("extremely"). With the exception of items belonging to the energy subscale, higher scores indicate more acute states of fatigue or fatigue (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).

[0220] Effective treatment will decrease tiredness and / or fatigue scores and / or increase energy subscale scores.

[0221] Treatment response can be assessed by using the above quantitative measurements, such as polysomnography or actigraphy, and / or the above questionnaires. Depending on the respective sleep scale, a significant decrease or increase in the total score, or a significant decrease in the prevalence, frequency, and impact on daily function, respectively, indicates treatment-induced improvement of sleep disorders.

[0222] A common test that can be used to assess psychomotor retardation or aspects of it is the Salpêtrière Retardation Rating Scale (SRRS).

[0223] To improve understanding of the pathophysiology and potential compensatory mechanisms involved, resting-state fMRI has been widely applied in patients with sleep disorders.

[0224] Alterations in the resting network can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0225] In insomnia patients, functional connectivity deficiencies have been observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Studies have shown that these networks contain important regions that integrate emotional and physical states, and functional connectivity deficiencies within these networks and / or between these networks and other brain regions may underlie patients' reduced alertness, subjective distress, and sleep continuity.

[0226] For example, sleep deprivation in healthy subjects leads to altered functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these alterations in brain functional connectivity bear some resemblance to vulnerability patterns in Alzheimer's disease patients.

[0227] The default mode network is affected in patients with hypersomnia: for example, in idiopathic hypersomnia, distinct DMN hubs, the precuneus and medial prefrontal cortex, show significant alterations, and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0228] A study investigating differences between night-shift and day-shift nurses revealed that circadian dysrhythmia contributes to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as reactivity and vigilance. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may lead to changes in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disorders.

[0229] Although it is technically difficult to perform functional brain imaging during sleep parasomnia events, precuneus differences have been observed in disorders of wakefulness that represent non-REM sleep parasomnias.

[0230] 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.

[0231] Resting-state fMRI studies in patients suffering from sleep-related breathing disorders such as obstructive sleep apnea (OSA) have demonstrated that some of the major contributors to OSA brain damage, namely chronic exposure to oxidative stress, intermittent hypoxia, hypocapnia and hypercapnia, and sleep fragmentation, can result in significant global and regional connectivity deficits, especially in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0232] Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Cerebellar and thalamic activity can also be observed, with additional activation of the red nucleus and brainstem.

[0233] In many cases, abnormal functional connectivity of resting-state networks involved in sleep regulation is also involved in psychomotor retardation. Thus, in accordance with the present invention, affecting these networks with the inventive therapy results in amelioration of sleep disorders and, if the treated patient suffers from psychomotor retardation, in amelioration of psychomotor retardation.

[0234] Clinical data from studies of patients suffering from TRD or postpartum depression (PPD) support that sleep disorders can be successfully treated.

[0235] Trials involving administration of 5-MeO-DMT specifically assessed the "reduced sleep" item of the MADRS (reflecting insomnia).

[0236] The "reduced sleep" item on the MADRS indicates the experience of a decreased duration or depth of sleep compared to the subject's own normal pattern when healthy. If the subject is sleeping normally, a score of 0 is assigned. A score of 2 reflects mild difficulty initiating sleep or mildly reduced, light, or disrupted sleep. A score of 4 means reduced or disrupted sleep for at least 2 hours. A score of 6 means less than 2-3 hours of sleep.

[0237] The combined MADRS "Decreased Sleep" item score across all eight patients in the study arm receiving the individualized dosing plan had a baseline of 25. One day after treatment (the earliest time point to assess the effect of treatment on sleep), the score had decreased to 12, corresponding to a 13-point or 52% improvement. Seven days after treatment, the score had decreased to 9, corresponding to a 16-point or 64% improvement.

[0238] MADRS "Decreased Sleep" item scores across all four patients in the 12 mg group were compiled from a baseline of 12. One day after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0239] Thus, the score for the scale item "reduced sleep", which is particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat sleep disorders, particularly in patients suffering from psychiatric or nervous system disorders.

[0240] Treatment of patients suffering from sleep disorders, particularly 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, particularly insomnia.

[0241] The reduction or elimination of psychomotor retardation in patients suffering from a sleep disorder, particularly insomnia, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0242] 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 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.

[0243] Reduction or elimination of psychomotor retardation in a patient suffering from a sleep disorder, particularly 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 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.

[0244] 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 within about 2 hours from 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 lasts for at least 6 days, particularly at least 14 days, more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0245] As mentioned above, psychomotor retardation is an important aspect in patients suffering from sleep disorder. Therefore, improving psychomotor retardation also leads to improving sleep disorder. Because psychomotor retardation also affects other aspects of sleep disorder, the inventors conclude that improving psychomotor retardation also contributes to the overall improvement of sleep disorder, especially insomnia.

[0246] In the case of idiopathic sleep disorders in patients who also suffer 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 that the CGI-S is decreased by at least one step. Preferably, the CGI-S is decreased by at least two steps and / or the score is 0. Particularly preferred is a decrease in the CGI-S by at least three steps and / or the score is 0.

[0247] 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, the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0248] The improvement of the idiopathic sleep disorder in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score in the patient who also suffers from associated psychomotor retardation, occurs within about 24 hours from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of the idiopathic sleep disorder in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score, preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0249] 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 score, is observed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and preferably persists for up to at least 14 days, and more preferably for up to at least 28 days.

[0250] In the case of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, improvement in the sleep disorder, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 24 hours of the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0251] In the case of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, improvement in the sleep disorder as reflected by a score of at least "much improved" on the CGI-I or PGI-I score preferably persists for at least 6 days, particularly at least 14 days, more preferably at least 28 days from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0252] Improvement in the case of idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation may also be assessed by any other measure reflecting changes in the quality or quantity of sleep as described above, for example the Pittsburgh Sleep Quality Index (PSQI).

[0253] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease of 5 or less.

[0254] Improvement in idiopathic sleep disorder in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI score, specifically to 5 or less, preferably occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, wherein the recall period extends from the time the acute hallucinatory experience subsided after the last administration to the time of evaluation.

[0255] Such improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, where the recall period spans from the time the acute hallucinatory experience abated after the last administration to the time of evaluation.

[0256] Improvement in idiopathic sleep disorders in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in PSQI score, is observed on the 1st day, e.g., about 24 hours, the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, where the recall period spans from the time the acute hallucinatory experience abated after the last administration to the time of evaluation.

[0257] Psychomotor retardation and sleep disorder, especially insomnia, are closely related to psychiatric and nervous system disorders. Both psychomotor retardation and sleep disorder, especially 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 the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, 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); chronic fatigue syndrome.

[0258] 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.

[0259] 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 the psychomotor retardation according to the invention results in amelioration of the condition associated with the psychomotor retardation.

[0260] Although psychomotor retardation may be considered a condition worthy of treatment independent of any other conditions, disorders, or symptoms that an individual may suffer from, some mental and nervous system disorders are associated with psychomotor retardation. In particular, the relationship between psychomotor retardation and mental disorders is bidirectional. Not only can mental disorders adversely affect a patient's psychomotor retardation, but psychomotor retardation may also be a factor in the onset, progression, and prognosis of a mental or nervous system disorder.

[0261] In many cases, the resting state network involved in psychomotor retardation is also involved in the above conditions.

[0262] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption results in the resetting of pathological, poorly connected brain connections as the network reconnects. New, healthy functional connections are established, and the effects are sustained.

[0263] Disorders characterized by depressive episodes There are a number of disorders that are characterized by depressive episodes.

[0264] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0265] 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 indicating a change from previous functioning, at least one of which is either (1) depressed mood or (2) loss of interest or pleasure, including symptoms such as psychomotor retardation.

[0266] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0267] Psychomotor retardation occurs in patients suffering from disorders characterized by depressive episodes.

[0268] Psychomotor retardation is included as a diagnostic criterion for disorders characterized by depressive episodes. This may be assessed as part of the HAM-D or MADRS assessment.

[0269] 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.

[0270] The items are outward sadness, verbal sadness, inner tension, decreased sleep, loss of appetite, difficulty concentrating, lethargy, inability to feel emotions, pessimistic thoughts, and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60.

[0271] The "apathy" item on the MADRS reflects difficulty in undertaking, or slowness in initiating and performing, daily activities.

[0272] A score of 0 means there is little difficulty in getting started and no sluggishness. If the patient has difficulty initiating activities, a score of 2 is assigned. A score of 4 means simple daily activities are difficult to initiate and require effort to perform. A score of 6 is assigned if there is complete lethargy and the patient is unable to do anything without assistance.

[0273] This MADRS scale item is particularly relevant for psychomotor retardation (ie, decreased energy and activity and decreased motivation).

[0274] 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 questions, but only the first 17 items (depressed mood, guilt, suicide, early insomnia, nighttime insomnia, late insomnia, work and interest, retardation, agitation, psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, total somatic symptoms, genital symptoms, hypochondriasis, weight loss, insight) are used for scoring.

[0275] For most questions, scores range from 0 to 4, with 4 indicating more acute signs of depression. Some questions range only up to 2. Total scores are tallied and may then be compared with previous scores or contrasted with a predefined cut-off score.

[0276] In relation to the item "retardation", the questionnaire assesses slowness of thought and speech, impaired concentration and reduced motor activity.

[0277] 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).

[0278] In patients suffering from a disorder characterized by depressive episodes, changes in functional connectivity have been observed within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes related to mental rumination; concentration and impaired physiological arousal.

[0279] Treating patients 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.

[0280] The reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by a depressive episode 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0281] 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.

[0282] The reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0283] The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of 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 score on the "apathy" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0284] Alternatively or additionally, psychomotor retardation, in particular reduction or elimination of retardation, in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in the score on at least the retardation item of the HAM-D 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.

[0285] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0286] 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 the score on at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0287] The reduction or elimination of psychomotor retardation in a patient suffering from a disorder characterized by a depressive episode, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0288] 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 related to 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0289] The reduction or elimination of psychomotor retardation in patients suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, 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 patients suffering from a disorder characterized by a depressive episode, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale 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.

[0290] As mentioned above, psychomotor retardation is closely related to the disorder characterized by depressive episodes.Therefore, the improvement of psychomotor retardation also leads to the improvement of the disorder characterized by depressive episodes.Since psychomotor retardation also affects other aspects of the disorder characterized by depressive episodes, the inventors conclude that the improvement of psychomotor retardation will also contribute to the overall improvement of the disorder characterized by depressive episodes.

[0291] Improvement in a disorder characterized by depressive episodes in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed on the 1st day, e.g., about 24 hours, 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0292] The improvement of the disorder characterized by a depressive episode in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score, occurs within 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 a depressive episode in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in the CGI-S score, 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.

[0293] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. It affects how a person feels, thinks, and behaves and can result in a variety of emotional and physical problems.

[0294] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder.

[0295] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two adequate treatment courses. In particular, the patient has not shown sufficient improvement after at least two adequate treatment courses, where at least one of the two courses is drug therapy. For example, the patient has not shown sufficient improvement after at least two adequate drug therapy courses. At least two past treatment courses were administered, particularly during ongoing depressive episodes.

[0296] Psychomotor retardation is a core feature of major depressive disorder (MDD) and is one of the nine symptoms listed to identify MDD in the DSM-V.

[0297] Clinical symptoms of psychomotor retardation in MDD include, among others, speech abnormalities, reduced eye contact and eye movements, and poor posture.

[0298] The presence of psychomotor retardation can be useful in guiding treatment planning, as there may be evidence that in these cases tricyclic antidepressants (TCAs) may provide a greater response than selective serotonin reuptake inhibitors (SSRIs).

[0299] Psychomotor retardation may be associated with greater symptom severity: a study of 291 MDD patients found that those with higher lifetime psychomotor retardation scores had more severe depression.

[0300] Psychomotor retardation in patients with MDD may be assessed as part of the assessment 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).

[0301] MDD can be characterized by disorders involving dysfunction of connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, limbic network, and somatomotor network. Functional connectivity differs significantly from that observed in healthy controls.

[0302] Treating patients suffering from MDD (including treatment-resistant forms of the disease) 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 the MDD.

[0303] The patient may suffer from moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. It is further believed that the patient may suffer from 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.

[0304] The 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, 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.

[0305] 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.

[0306] A reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from MDD is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0307] The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from MDD, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from MDD, as reflected by an improvement in the score on the "apathy" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0308] Alternatively or additionally, psychomotor retardation, in particular reduction or elimination of psychomotor retardation, in a patient suffering from MDD is reflected by an improvement in the score on at least the retardation item of the HAM-D 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.

[0309] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from MDD, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from MDD, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0310] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from MDD is reflected by an improvement in the score on at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0311] 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 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, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0312] 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 related to 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0313] The reduction or elimination of psychomotor retardation in patients suffering from MDD, as reflected by an improvement in the mean score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, occurs within about 2 hours of 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 score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0314] As mentioned above, psychomotor retardation is closely related to MDD.Therefore, improving psychomotor retardation also leads to improving MDD.Psychomotor retardation also affects other aspects of MDD, so we conclude that improving psychomotor retardation, especially reducing or eliminating psychomotor retardation, will also contribute to the overall improvement of MDD.

[0315] Improvement in MDD in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0316] Improvement in MDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0317] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT or a pharma- ceutically acceptable salt thereof can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from MDD associated with psychomotor retardation.

[0318] Preferably, patients suffering from MDD associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0319] Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). Bipolar disorder is a relapsing, chronic illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0320] BD is classified as bipolar I disorder if there has been at least one manic episode with or without depressive episodes. BD is classified as bipolar II disorder if there has been at least one hypomanic episode (but no full manic episode) and one major depressive episode. If these symptoms are due to drugs or medical problems, it is not diagnosed as bipolar disorder.

[0321] Patients suffering from BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0322] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two adequate treatment courses. In particular, the patient has not shown sufficient improvement after at least two adequate treatment courses, where at least one of the two courses is drug therapy. For example, the patient has not shown sufficient improvement after at least two adequate drug therapy courses. At least two past treatment courses were administered, particularly during ongoing depressive episodes.

[0323] Psychomotor retardation is a core 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.

[0324] A study comparing bipolar depressed patients with age-matched unipolar depressed patients found that bipolar disorder was associated with higher psychomotor retardation scores than unipolar depression with the same depression severity scores.

[0325] Psychomotor retardation in patients with BD can be assessed as part of the assessment of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, can be further assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0326] Patients suffering from bipolar disorder display characteristic abnormal intrinsic organization and interconnectivity of resting-state networks.

[0327] Compared to healthy controls, resting-state functional magnetic resonance imaging studies demonstrated altered functional connectivity of specific regions within and / or between the default mode network, the salience network, and the central executive network.

[0328] Treating patients suffering from BD (including treatment-resistant forms of the disease) 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.

[0329] Typically, patients with BD, whether diagnosed with bipolar II or bipolar I disorder, experience an ongoing major depressive episode.

[0330] The severity of an ongoing major depressive episode may be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score of 19 or greater, such as 24 or greater, particularly 37 or greater.

[0331] A reduction or elimination of psychomotor retardation in a patient suffering from BD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0332] The reduction or elimination of psychomotor retardation in a patient suffering from BD 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 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.

[0333] A reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from BD is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0334] The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from bipolar disorder, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, as reflected by an improvement in the score on the "apathy" item of the MADRS, in patients suffering from BD, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0335] Alternatively or additionally, psychomotor retardation, in particular reduction or elimination of retardation, in a patient suffering from BD is reflected by an improvement in score on at least the retardation item of the HAM-D 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.

[0336] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from BD, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from BD, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0337] Alternatively or additionally, a reduction or psychomotor retardation in a patient suffering from BD 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.

[0338] 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 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 BD, 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.

[0339] Alternatively or additionally, the reduction or 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 related to 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, 7 days, 14 days, and / or 28 days 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 BD, as reflected by an improvement in the mean score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, occurs within about 2 hours of 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 score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0341] As mentioned above, psychomotor retardation is closely related to BD. Therefore, improvement of psychomotor retardation will lead to improvement of BD. Since psychomotor retardation also affects other aspects of BD, the inventors conclude that improvement of psychomotor retardation will also contribute to overall improvement of BD.

[0342] Improvement in BD in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0343] Improvement in BD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0344] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from bipolar disorders, such as bipolar I disorder and bipolar II disorder associated with psychomotor retardation.

[0345] Preferably, patients suffering from bipolar disorders, such as bipolar I disorder and bipolar II disorder associated with psychomotor retardation, do not experience treatment-emergent mania or hypomania.

[0346] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within 4 weeks after delivery. Over 50% of women may experience a short period of low mood or tearfulness after giving birth, while a small group of women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be around 15%.

[0347] Patients suffering from PPD may suffer from a treatment-resistant form of the disorder.

[0348] Postpartum depression is also defined as a major depressive episode within 4 weeks after delivery. Thus, psychomotor retardation is a core feature of postpartum depression and is one of the nine symptoms listed to identify a major depressive episode in the DSM-V.

[0349] Psychomotor retardation in patients with PPD may be assessed as part of the assessment 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).

[0350] 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 functional connectivity disorders of resting-state networks, for example within and / or between the default mode network and the frontoparietal network.

[0351] Treating patients suffering from PPD (including treatment-resistant forms of the disease) 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 PPD.

[0352] The patient may have moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. It is further believed that the patient may have severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] The 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, 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.

[0357] 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.

[0358] A reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from PPD is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0359] The reduction or elimination of psychomotor retardation, particularly lethargy, in a patient suffering from PPD, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly lethargy, in a patient suffering from PPD, as reflected by an improvement in the score on the "apathy" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0360] Alternatively or additionally, psychomotor retardation, in particular reduction or elimination of retardation, in a patient suffering from PPD is reflected by an improvement in score on at least the retardation item of the HAM-D 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.

[0361] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from PPD, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from PPD, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0362] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PPD is reflected by an improvement in the 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 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 pharmacologic acceptable salt thereof.

[0363] 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 within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0364] 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 related to 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0365] The reduction or elimination of psychomotor retardation in patients with PPD, as reflected by an improvement in the mean score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, occurs within about 2 hours of 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 score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0366] As mentioned above, psychomotor retardation is closely related to PPD.Therefore, improving psychomotor retardation also leads to improving PPD.Psychomotor retardation also affects other aspects of PPD, so we conclude that improving psychomotor retardation also contributes to the overall improvement of PPD.

[0367] Improvement in PPD in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 29 after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0368] Improvement in PPD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0369] Psychomotor retardation further impairs maternal function.

[0370] Maternal functioning may be assessed, for example, using the Barkin Index of Maternal Function (BIMF). This index was designed to measure functioning during the year following childbirth. The BIMF is a self-report measure of functioning consisting of 20 items. Each item is assigned a score from 0 to 6, with a maximum total score of 120. The higher the score, the better the maternal functioning is assessed.

[0371] The BIMF identifies the following key areas of functioning for mothers during the postpartum period: self-care, care of the infant, mother-infant interaction, maternal emotional well-being, social support, control, and adaptation.

[0372] A BIMF score of 95 or less is considered herein to represent minimal impairment of maternal function, a score of 80 or less is considered herein to represent impairment of maternal function, and a score of 65 or less is considered herein to represent severe impairment of maternal function.

[0373] The inventors determined that an increased score on the MADRS "lethargy" item adversely affected both aspects of maternal functioning (maternal ability related to interactions with infant(s) and maternal self-care).

[0374] An increase in the score on the MADRS "apathy" item impairs self-care, emotional well-being, and control. Conversely, an improvement on this MADRS item translates to an improvement in maternal functioning, particularly in the BIMF domains of emotional well-being, social support, and / or control.

[0375] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in psychomotor retardation, in particular reduction or elimination of apathy.

[0376] The inventors further conclude that reduction or elimination of lethargy by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the MADRS total score, but also by an increase in the BIMF score.

[0377] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0378] Improved maternal function in patients with PPD is reflected by an improvement in at least 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.

[0379] The improvement in maternal function in patients with PPD, as reflected by at least an improvement in the BIMF total score, occurs within about 6 days of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement in maternal function, as reflected by at least an improvement in the BIMF total score, preferably persists for at least 14 days, more preferably for at least 28 days, of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0380] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from PPD associated with psychomotor retardation.

[0381] Preferably, patients suffering from PPD associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0382] 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 feelings of sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0383] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0384] Compared to controls, patients with seasonal affective disorder show significant season-independent impairments in tasks measuring working memory, cognitive processing speed, and motor speed.

[0385] Sensorimotor dysfunction has been reported in depressed subjects compared with healthy controls.

[0386] Psychomotor symptoms associated with depressed mood are often thought to affect not only the execution of motor responses but also the speed of thought.

[0387] Seasonal affective disorder is associated with psychomotor retardation, as depressive episodes may meet DSM-V criteria for a major depressive episode.

[0388] Psychomotor retardation in patients suffering from seasonal affective disorder may be assessed as part of the assessment 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).

[0389] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0390] Treating patients suffering from seasonal affective disorder (including treatment-resistant forms of the disease) and associated psychomotor retardation with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation and leads to improvement of the seasonal affective disorder.

[0391] The reduction or elimination of psychomotor retardation in a patient 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0392] 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.

[0393] The reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0394] The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from seasonal affective disorder, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, as reflected by an improvement in the score on the "apathy" item of the MADRS, in patients suffering from seasonal affective disorder, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0395] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from seasonal affective disorder is reflected by an improvement in score on at least the retardation item of the HAM-D 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.

[0396] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0397] Alternatively or additionally, a reduction or 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 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.

[0398] 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 Salpêtrière Retardation Rating Scale (SRRS), 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, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0399] Alternatively or additionally, the reduction or psychomotor slowing 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 at least motor slowing 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0400] The reduction or elimination of psychomotor retardation in patients suffering from seasonal affective disorder, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, 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 patients suffering from seasonal affective disorder, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale 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.

[0401] As mentioned above, psychomotor retardation is closely related to seasonal affective disorder. Therefore, improving psychomotor retardation also leads to improving seasonal affective disorder. Because psychomotor retardation also affects other aspects of seasonal affective disorder, the inventors conclude that improving psychomotor retardation also contributes to the overall improvement of seasonal affective disorder.

[0402] 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 on the 1st day, e.g., on 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.

[0403] The improvement of seasonal affective disorder in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of seasonal affective disorder in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0404] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT or a pharma- ceutically acceptable salt thereof can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from seasonal affective disorder associated with psychomotor retardation.

[0405] Preferably, patients suffering from seasonal affective disorder associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0406] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed when depression is present for the majority of days over a period of at least two years. Any symptom-free periods last less than two months.

[0407] During a depression, two or more of the following must be present: 1. Feeling hopeless; 2. Low energy or fatigue; 3. Low self-esteem; 4. Decreased (insomnia) or increased (hypersomnia) sleep; 5. Loss of appetite or overeating; 6. Difficulty making decisions or poor concentration.

[0408] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0409] According to the DSM-V, persistent depressive disorder is characterized by criteria for major depressive disorder that may be present continuously for two years.

[0410] Persistent depressive disorder is associated with psychomotor retardation as depressive episodes may meet DSM-V criteria for a major depressive episode.

[0411] Psychomotor retardation in patients suffering from PDD can be assessed as part of the assessment of the HAM-D or MADRS. Psychomotor retardation, or at least aspects thereof, can be further assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS) or the Motor Agitation and Retardation Scale (MARS).

[0412] In patients suffering from persistent depressive disorder, changes in functional connectivity have been observed within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes related to mental rumination; concentration and impairments in physiological arousal.

[0413] Functional connectivity deficiencies are observed within and between the DMN, salience network, executive control network, and limbic network, and functional connectivity differs significantly from that observed in healthy controls.

[0414] Treating patients suffering from PDD (including treatment-resistant forms of the disease) 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 PDD.

[0415] The 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- 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.

[0416] 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.

[0417] A reduction or elimination of psychomotor retardation, particularly apathy, in a patient suffering from PDD is reflected by an improvement in the score for at least the "apathy" item of the MADRS about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0418] The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from PDD, as reflected by an improvement in the score on the "apathy" item of the MADRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly apathy, in patients suffering from PDD, as reflected by an improvement in the score on the "apathy" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0419] Alternatively or additionally, the psychomotor retardation, in particular the reduction or elimination of psychomotor retardation, in a patient suffering from PDD is determined to occur within 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, This is reflected at least by an improvement in the score on the HAM-D delay item.

[0420] The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from PDD, as reflected by an improvement in the retardation item score of the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The reduction or elimination of psychomotor retardation, particularly retardation, in a patient suffering from PDD, as reflected by an improvement in the retardation item score of the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0421] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PDD is reflected by an improvement in the score on at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0422] 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 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, 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.

[0423] 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 related to 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0424] The reduction or elimination of psychomotor retardation in patients with PDD, as reflected by an improvement in the mean score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, occurs within about 2 hours of 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 score on at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0425] As mentioned above, psychomotor retardation is closely related to PDD.Therefore, improving psychomotor retardation also leads to improving PDD.Psychomotor retardation also affects other aspects of PDD, so we conclude that improving psychomotor retardation, especially reducing or eliminating psychomotor retardation, will also contribute to the overall improvement of PDD.

[0426] Improvement in PDD in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0427] Improvement in PDD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0428] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT or a pharma- ceutically acceptable salt thereof can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from persistent depressive disorders associated with psychomotor retardation.

[0429] Preferably, patients suffering from persistent depressive disorder associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0430] Mental and behavioral disorders resulting from the use of psychoactive substances A substance use disorder (SUD) is a mental disorder that affects human behavior and causes a person to be unable to control their use of substances, such as legal or illegal drugs, alcohol, or medicines. Symptoms can range from moderate to severe, with addiction being the most severe form of SUD.

[0431] Patients suffering from SUDs may suffer from treatment-resistant forms of the disorder.

[0432] Psychomotor retardation occurs in patients suffering from certain mental and behavioral disorders resulting from the use of psychoactive substances.

[0433] 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.

[0434] A large study of regular cannabis users found that psychomotor retardation was one of the most common symptoms of cannabis withdrawal, although with a lifetime prevalence of only 1%.

[0435] Resting-state functional connectivity (rsFC) has been found to be altered in patients with psychomotor retardation as well as in those with SUDs.

[0436] Psychomotor retardation, or at least aspects thereof, may also be assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS).

[0437] Treating patients suffering from SUD (including treatment-resistant forms of the disease) 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.

[0438] The 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, 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.

[0439] 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.

[0440] 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 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.

[0441] 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 within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0442] 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, the inventors conclude that improving psychomotor retardation will also contribute to the overall improvement of substance use disorder.

[0443] Improvement in SUD in patients suffering from psychomotor retardation, as reflected by a decrease in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0444] The improvement of SUD in a patient suffering from psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of psychomotor retardation in a patient suffering from SUD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0445] Psychotic disorders Psychotic disorders are severe mental disorders that cause abnormalities in thinking and perception. Psychotic disorders are characterized by marked impairments in reality testing and changes in behavior that manifest as positive symptoms such as persistent delusions, persistent hallucinations, disorganized thinking (usually manifested as disorganized speech), markedly disorganized behavior, and experiences of passivity and domination, negative symptoms such as blunted or flat affect and decreased motivation, and psychomotor disorders.

[0446] Patients suffering from a psychotic disorder may suffer from a treatment-resistant form of the disorder.

[0447] The DSM-V describes symptoms of psychomotor retardation, such as deficits in language and motor responses, as the core feature that defines a psychotic disorder. Schizophrenia is an example of a primary psychotic disorder in which psychomotor retardation is a prominent feature.

[0448] Psychomotor retardation is also seen in other psychotic disorders, such as schizoaffective disorder.

[0449] Psychomotor retardation or at least aspects thereof may also be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0450] Functional magnetic resonance imaging of the brain's resting-state network in patients with psychosis reveals significant alterations in distinct regions within and / or between the central executive, default mode, and salience networks. Alterations in the resting-state network can be identified even in patient populations at risk for psychosis.

[0451] Treating patients suffering from a psychotic disorder (including treatment-resistant forms of the disease) 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 psychotic disorder.

[0452] The 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0453] 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.

[0454] Reduction or elimination of psychomotor retardation in a patient suffering from a psychotic disorder 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 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.

[0455] 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 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, 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.

[0456] 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 also leads to the improvement of psychotic disorder. Because psychomotor retardation also affects other aspects of psychotic disorder, the inventors conclude that the improvement of psychomotor retardation also contributes to the overall improvement of psychotic disorder.

[0457] 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, 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.

[0458] The improvement of the psychotic disorder in a patient who also suffers from an associated psychomotor retardation, as reflected by a reduction in the CGI-S score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of the psychotic disorder in a patient who also suffers from an associated psychomotor retardation, as reflected by a reduction in the CGI-S score, preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from 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 preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in a patient suffering from a psychotic disorder characterized by mania or hypomania and associated with psychomotor retardation.

[0460] 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.

[0461] Schizophrenia is a severe mental health condition characterized by disturbances in multiple mental modalities including perception, self-experience, motivation, emotion, and behavior. Psychomotor disturbances, including catatonia, may be present.

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

[0463] Psychomotor retardation and slowing are also core features of schizophrenia and are classified as one of the "negative symptoms" that characterize the disease. Manifestations can range from slowed movements to severe catatonia.

[0464] There is evidence to suggest that psychomotor retardation is associated with more severe illness in schizophrenia and decline in semantic and episodic memory.

[0465] Abnormalities in resting-state functional connectivity, particularly within and / or between the default mode network, frontoparietal network, and salience network, have been reported in individuals with schizophrenia.

[0466] Psychomotor retardation or at least aspects thereof may also be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0467] Treating patients suffering from schizophrenia (including treatment-resistant forms of the disease) 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 schizophrenia.

[0468] The 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, 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.

[0469] 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.

[0470] Reduction or elimination of psychomotor retardation in a patient suffering from schizophrenia 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 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.

[0471] 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 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, 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.

[0472] As mentioned above, psychomotor retardation is closely related to schizophrenia. Therefore, the improvement of psychomotor retardation also leads to the improvement of schizophrenia. Since psychomotor retardation also affects other aspects of schizophrenia, the inventors conclude that the improvement of psychomotor retardation will also contribute to the overall improvement of schizophrenia.

[0473] 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, 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.

[0474] The improvement of schizophrenia in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of schizophrenia in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0475] In comparison to other hallucinogens such as LSD, psilocybin or DMT, 5-MeO-DMT or a pharma- ceutically acceptable salt thereof can preferably be administered using the administration schemes described herein without significant risk of inducing mania or hypomania in patients suffering from schizophrenia associated with psychomotor retardation.

[0476] Preferably, patients suffering from schizophrenia associated with psychomotor retardation do not experience treatment-emergent mania or hypomania.

[0477] Dementia Dementia is caused by abnormal changes in the brain that lead to a decline in cognitive abilities and affect behavior, emotions, and interpersonal relationships. The condition is generally characterized by a loss of memory, language, problem-solving, and other thinking skills that is severe enough to interfere with daily life.

[0478] Psychomotor slowing is a key feature of the dementia syndrome.

[0479] Psychomotor retardation or at least aspects thereof may also be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0480] Dementia affects various functional and structural connectivity networks in the brain, as can be shown by magnetic resonance imaging studies: changes are observed within and / or between the default mode network (DMN), the salience network, and the central executive network (CEN).

[0481] 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 leads to amelioration of the dementia.

[0482] The 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- ceutical acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0483] 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.

[0484] Reduction or elimination of psychomotor retardation in a patient suffering from dementia is reflected by an improvement in the score on at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0485] 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 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, as reflected by at least an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0486] As mentioned above, psychomotor retardation occurs in patients suffering from dementia.Therefore, improving psychomotor retardation also leads to improving dementia.Since psychomotor retardation also affects other aspects of dementia, the inventors conclude that improving psychomotor retardation also contributes to the overall improvement of dementia.

[0487] 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- 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.

[0488] The improvement in dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0489] Alzheimer's dementia (AD) is a highly prevalent neurodegenerative disorder with an insidious onset and gradual progression of cognitive impairment. The percentage of neurocognitive impairment attributable to Alzheimer's disease ranges from approximately 60% to more than 90%, depending on the circumstances and diagnostic criteria. Decline in learning and memory is the primary early feature, and the decline is progressive.

[0490] Psychomotor slowing is a key feature of dementia syndromes such as Alzheimer's disease, the pathological driver of which may be a slowing of sensorimotor and decision processes.

[0491] A study of 148 patients with mild cognitive impairment and age-matched controls found that the presence of psychomotor retardation significantly increased the risk of conversion to Alzheimer's dementia.

[0492] Psychomotor retardation or at least aspects thereof may also be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0493] 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, supporting the idea that AD is a disconnected brain syndrome. In particular, alterations within and / or between the default mode network (DMN), salience network, and central executive network (CEN) are observed in both AD patients and individuals at high risk for developing AD.

[0494] Thus, affecting these networks through the treatment of the present invention leads to improvement in the symptoms of AD, as well as improvement in psychomotor retardation.

[0495] 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 leads to amelioration of Alzheimer's dementia.

[0496] The reduction or elimination of psychomotor retardation in a patient suffering from AD is observed 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.

[0497] 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 lasts for up to at least 6 days, particularly up to at least 14 days, and more preferably up to at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0498] Reduction or elimination of psychomotor retardation in a patient suffering from AD is reflected by an improvement in the score on at least the Salpêtrière Retardation Rating Scale (SRRS) about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0499] 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 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, 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.

[0500] As mentioned above, psychomotor retardation is an important aspect in patients suffering from AD.Therefore, improving psychomotor retardation also leads to improvement of AD.Since psychomotor retardation also affects other aspects of AD, the inventors conclude that improving psychomotor retardation also contributes to the overall improvement of AD.

[0501] Improvement in AD in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0502] Improvement of AD in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0503] Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and the regulation of automatic bodily functions.

[0504] Psychomotor slowing plays an important role in dementia with Lewy bodies (DLB). In DLB, psychomotor slowing can be demonstrated by visual and attention disorders that also contribute to hallucinations. DLB is characterized by worse psychomotor impairment than Alzheimer's disease.

[0505] Psychomotor retardation or at least aspects thereof may also be assessed, for example, by the Salpêtrière Retardation Rating Scale (SRRS).

[0506] In patients with DLB, alterations in the resting state network (RSN) can be identified. Functional MRI studies show changes in functional connectivity within and / or between the default mode network, salience network, executive network, and basal ganglia / limbic network.

[0507] 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.

[0508] The 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, 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.

[0509] 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.

[0510] Reduction or elimination of psychomotor retardation in a patient suffering from DLB is reflected by an improvement in the score on at least the Salpêtrière Retardation Rating Scale (SRRS) 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.

[0511] The reduction or elimination of psychomotor retardation in a patient suffering from DLB, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0512] As mentioned above, psychomotor retardation is an important aspect in patients suffering from DLB.Therefore, improving psychomotor retardation also leads to improvement of DLB.Since psychomotor retardation also affects other aspects of DLB, we conclude that improving psychomotor retardation also contributes to the overall improvement of DLB.

[0513] Improvement in DLB in patients who also suffer from associated psychomotor retardation, as reflected by a decrease in CGI-S score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically 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-ceutically acceptable salt thereof.

[0514] Improvement in DLB in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0515] 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 resulting from impaired blood flow to the brain.

[0516] Psychomotor retardation has been noted as a clinical feature consistent with a diagnosis of possible vascular dementia according to NINDS-AIREN (National Institute of Neurological Disorders and Stroke / Association Internationale pour la Recherche et l'Enseignement en Neurosciences research) criteria.

[0517] Psychomotor retardation is particularly common when vascular dementia affects subcortical regions.

[0518] Psychomotor retardation, or at least aspects thereof, may be assessed, for example, by using the Salpêtrière Retardation Rating Scale (SRRS).

[0519] Functional magnetic resonance imaging reveals altered functional connectivity of resting-state networks after cerebrovascular accident. Patients suffering from severe or mild vascular neurocognitive impairment show abnormal functional connectivity within the DMN and other resting-state networks.

[0520] Treatment of 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 leads to improvement of the vascular dementia.

[0521] The reduction or elimination of psychomotor retardation in a patient suffering from vascular dementia is observed 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.

[0522] 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.

[0523] Reduction or elimination of psychomotor retardation in a patient suffering from vascular dementia is reflected by an improvement in the score on at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0524] 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 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 patients suffering from vascular dementia, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0525] As mentioned above, psychomotor retardation is an important aspect in patients suffering from vascular dementia.Therefore, improving psychomotor retardation also leads to improving vascular dementia.Since psychomotor retardation also affects other aspects of vascular dementia, the inventors conclude that improving psychomotor retardation also contributes to the overall improvement of vascular dementia.

[0526] 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, 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.

[0527] The improvement of vascular dementia in patients who also suffer from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0528] Parkinson's disease dementia is characterized by changes in thinking and behavior in patients diagnosed with Parkinson's disease, a disease characterized by slowly progressive movement problems, most commonly involving slowing of movements, a tremor present at rest, and an unsteady gait that can lead to falls.

[0529] Parkinson's disease dementia is also associated with psychomotor retardation.

[0530] Research has shown that there is functional reorganization of resting network in patients with Parkinson's disease dementia, which is essential for generating and maintaining efficient behavioral and cognitive performance. Levodopa, which improves the clinical condition of Parkinson's patients, has the potential to affect the functional connectivity of resting network in Parkinson's patients.

[0531] Treatment of patients 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 leads to improvement of the Parkinson's disease dementia.

[0532] The 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, the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0533] The reduction or elimination of psychomotor retardation in a patient suffering from Parkinson's disease dementia occurs within 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.

[0534] Improvement in psychomotor retardation in patients suffering from Parkinson's disease dementia, as reflected by a reduction in CGI-S score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmacologic acceptable salt thereof.

[0535] The improvement in psychomotor retardation in patients with Parkinson's disease dementia, as reflected by a reduction in CGI-S score, occurs within 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 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.

[0536] 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 1st day, e.g., about 24 hours, 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0537] 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 within 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, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0538] As mentioned above, psychomotor retardation is an important aspect of Parkinson's disease dementia. Therefore, improving psychomotor retardation also leads to improving Parkinson's disease dementia. Because psychomotor retardation also affects other aspects of Parkinson's disease dementia, the present inventors conclude that improving psychomotor retardation also contributes to the overall improvement of Parkinson's disease dementia.

[0539] 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 on the 1st day, e.g., about 24 hours, the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0540] 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 within about 24 hours of 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 for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0541] Parkinson's disease Parkinson's disease (PD) is a disease characterized by slowly progressive movement disorders, most commonly involving slowing of movement, a tremor present at rest, and an unsteady gait that can lead to falls.

[0542] Psychomotor retardation is a cardinal feature of subcortical disorders such as Parkinson's disease (PD).

[0543] 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).

[0544] Resting-state network analyses using functional magnetic resonance imaging indicate that Parkinson's disease-related cognitive impairments are associated with patterns of altered connectivity within and / or between resting-state functional connectivity networks, such as the default mode network, the dorsal attention network, or the frontoparietal network.

[0545] 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.

[0546] The reduction or elimination of psychomotor retardation in a patient suffering from PD is observed 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.

[0547] 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 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.

[0548] 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 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.

[0549] The reduction or elimination of psychomotor retardation in a patient suffering from PD, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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, as reflected by an improvement in the score on the Salpêtrière Retardation Rating Scale (SRRS), 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.

[0550] Alternatively or additionally, the reduction or elimination of psychomotor retardation in a patient suffering from PD is reflected by at least an improvement in Digit Symbol Substitution Test (DSST) score 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.

[0551] The reduction or elimination of psychomotor retardation in a patient suffering from PD, as reflected by an improvement in the Digit Symbol Substitution Test (DSST) score, 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, 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.

[0552] As mentioned above, psychomotor retardation is an important aspect in patients suffering from PD.Therefore, improving psychomotor retardation will lead to the improvement of PD.Since psychomotor retardation also affects other aspects of PD, the inventors conclude that improving psychomotor retardation will also contribute to the overall improvement of PD.

[0553] 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, 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.

[0554] The improvement in psychomotor retardation in a patient suffering from PD, as reflected by a reduction in the CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement in psychomotor retardation in a patient suffering from PD, as reflected by a reduction in the CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0555] Chronic fatigue syndrome Fatigue describes exhaustion, weariness, and reduced energy. Fatigue is experienced as a weakening or depletion of a person's physical or mental resources. Although considered normal after a period of strenuous activity, mental or physical fatigue may occur in the absence of such activity as a symptom of a health condition.

[0556] Furthermore, chronic fatigue that is exacerbated by activity is a prominent symptom of chronic fatigue syndrome, a disorder in which severe fatigue is accompanied by neurocognitive, autonomic, and immune symptoms.

[0557] Various abnormalities in normal sleep patterns have been reported in patients with chronic fatigue syndrome that may act as perpetuating factors.

[0558] Symptoms of chronic fatigue syndrome also include psychomotor slowing.

[0559] Patients suffering from chronic fatigue syndrome exhibit abnormalities in resting-state functional connectivity that correlate significantly with the severity of their chronic fatigue.

[0560] Treating patients suffering from chronic fatigue syndrome (including treatment-resistant forms of the disease) 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.

[0561] The 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0562] 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.

[0563] 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 at least the Salpetriere Retardation Rating Scale (SRRS) 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.

[0564] 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 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 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 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] 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 related to 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, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0566] The reduction or elimination of psychomotor retardation in patients suffering from chronic fatigue syndrome, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale associated with motor retardation, 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 patients suffering from chronic fatigue syndrome, as reflected by an improvement in the mean score of at least the Motor Agitation and Retardation Scale (MARS) subscale 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.

[0567] As mentioned above, psychomotor retardation is closely related to chronic fatigue syndrome. Therefore, the improvement of psychomotor retardation also leads to the improvement of chronic fatigue syndrome. Because psychomotor retardation also affects other aspects of chronic fatigue syndrome, the inventors conclude that the improvement of psychomotor retardation, especially the reduction or elimination of psychomotor retardation, will also contribute to the overall improvement of chronic fatigue syndrome.

[0568] 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- 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.

[0569] The improvement of chronic fatigue syndrome in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. The improvement of chronic fatigue syndrome in a patient who also suffers from associated psychomotor retardation, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, from the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. EXAMPLES

[0570] 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.

[0571] 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 solution volume of 200 μl. A typical target dose 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.

[0572] 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.

[0573] 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.

[0574] 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.

[0575] 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.

[0576] Step 6: To prepare for administration, ask the patient to first inhale deeply and exhale completely 1-2 times, concluding 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, then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0577] 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.

[0578] 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. After stirring at 7-12° C. for 10 min, crystallization occurred. Following stirring at 7-12° C. for 1 h, the batch was 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.

[0579] Analysis further indicates that the levels of individual impurities were below 0.10% area. Solvent analysis of the sample indicated an MTBE level of 17 ppm.

[0580] Example 3 – Preparation of 5-MeO-DMT hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0581] 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.

[0582] 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.

[0583] An off-white crystalline material was obtained.

[0584] 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.

[0585] 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.

[0586] 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.

[0587] 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 homogenized again in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined and diluted with ice-cold membrane preparation buffer (1:100 w / v) 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 to wash the tissue (20,500xg, 10 min). 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 consisted of 50 mM Tris-HCl (pH 7.7), 4 mM CaCl2, and 0.1% ascorbic acid. Assay buffer consisted of 50 mM Tris (pH 7.7), 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM pargyline.

[0588] 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).

[0589] 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.

[0590] 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).

[0591] 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.

[0592] 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.

[0593] 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).

[0594] 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.

[0595] Membrane-bound radioactivity was collected and measured as above, and data analysis was also performed as above.

[0596] 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.

[0597] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0598] 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.

[0599] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0600] 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.

[0601] 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).

[0602] 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 received 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 at 1, 1.5, 2, 3, and 4 hours after administration.

[0603] 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.

[0604] 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).

[0605] Table 1 below shows the median plasma concentration percentages of Cmax measured at the indicated time points. [Table 1]

[0606] Pharmacokinetic measurements were also performed using a dosing scheme based on ascending dose titration, with substantially similar results.

[0607] 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.

[0608] Substantially similar observations were made when subjects undergoing an escalating titration scheme were included.

[0609] 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 day 7 after dosing.

[0610] 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.

[0611] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission 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 percent change from baseline at day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0612] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0613] 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%).

[0614] 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.

[0615] The results are summarized in the table below. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0616] 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).

[0617] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0618] More specifically, on day 0, patients will receive up to three doses of 5-MeO-DMT: 6 mg, 12 mg, and 18 mg. 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 of 75) after 6 mg of treatment; 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 range but not clinically significant, as determined by the investigator. 3. Similarly, the third dose (18 mg) is administered only if: a. Failure to achieve a peak experience (total score of 75) after administration of 12 mg; 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 range but not clinically significant, as determined by the investigator.

[0619] Patients will be assessed post-injection for peak hallucinatory experience (based on the patient-rated visual analog scale PE scale), sedation, and other endpoints. Follow-up visits are scheduled 1 and 7 days after the date of injecting.

[0620] All patients considered for participation in a clinical trial must meet the following criteria: 1. Females aged 18-45 years (inclusive) at the time of screening. 2. Body mass index (BMI) at screening: 18.5-35 kg / m 2 The range is inclusive. 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 determined by the Mini-Institute for Mental Illnesses (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 lactating or actively breastfeeding at screening, 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 which 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 total abstinence (abstain completely from heterosexual intercourse) or use a medically accepted method of contraception that is highly effective (failure rate <1%) for 30 days prior to and 90 days after 5-MeO-DMT administration. 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 7 days after the end of the study and agree to keep any psychotherapy unchanged during the study.

[0621] 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 study investigator, renders the patient unsuitable for the study. 2. Have 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 significant risk for suicide as determined by a study psychiatrist or licensed psychologist based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS). 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. Known allergy or hypersensitivity to 7.5-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 failure, 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 exam, vital signs, ECG, or clinical laboratory parameters that would cause the study physician to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day prior to the study (day -1) are pregnant or plan to become pregnant during the study and up to 90 days after 5-MeO-DMT administration. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0622] 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.

[0623] 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.

[0624] 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).

[0625] 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.

[0626] Secondary endpoints included the antidepressant effects of 5-MeO-DMT assessed by: Antidepressant effects of 5-MeO-DMT assessed by: The proportion of patients in remission (MADRS 10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Percent change from baseline in MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; Proportion of responders (a 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Percent change from baseline in Clinical Global Impression-Severity (CGI-S) scores 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 Functioning (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. - 5-MeO-DMT and bufotenin exposure in blood obtained on the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, on days 1 and 7; Safety and tolerability of 5-MeO-DMT as assessed by: Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, clinical safety laboratory tests, and peak expiratory flow measurements. Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each dose of the study drug) and as part of the discharge assessment on Day 0; Percent change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the C-SSRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the YMRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score 75); ·Challenging Experience Questionnaire (CEQ), ·Mystical Experience 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).

[0627] 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.

[0628] 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.

[0629] 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, according to the individualized dosing plan design. A PES score of 85.7 was achieved at this dose, which was 75, indicating that the patient had experienced a peak hallucinatory experience and completed the IDR.

[0630] 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]

[0631] 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).

[0632] Similarly, improvements were seen in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt and tension.

[0633] Furthermore, improvement in maternal function was evidenced by an improvement in the BIMF scores recorded on day 7, as outlined in Table 5 , with the total score improving by 14% from 92 to 105 (out of a possible total of 120).

[0634] 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.

[0635] Here, significant improvements in self-care, emotional well-being, and management were achieved, ranging from 18% (management) to 44% (self-care). These improvements strengthen the relationship between improvement in depressive items assessed by the MADRS and improvement in maternal functioning.

[0636] It should be noted that the patients' scores were already relatively high before treatment: in some areas of functioning, scores were at or near the maximum (see Table 6), so the extent of improvement with treatment was limited. [Table 9-1] [Table 9-2] [Table 10]

[0637] Summary and Conclusion A. An individualized dosing regimen of 6 mg of inhaled 5-MeO-DMT followed by 12 mg of 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. With C.IDR, patients experienced clinical remission within 2 hours of 5-MeO-DMT administration, far superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date. D. Significant clinical responses were sustained over a 7-day follow-up period, although 5-MeO-DMT was only administered once and is no longer present in the body to be effective during this time frame (see pharmacokinetic data in Example 6 above). This observation supports the excellent clinical profile of 5-MeO-DMT, allowing for convenient dosing intervals. E. In addition to the antidepressant effects, endpoints assessing other symptoms (e.g., hypochondriasis, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders. F. In addition to the antidepressant effect, endpoints assessing maternal functioning, such as self-care, emotional well-being and control, as assessed using the BIMF, were also positively affected, supporting the additional benefits of 5-MeO-DMT for patients with PPD, beyond just its improvement in core depressive symptoms.

[0638] The embodiments clearly demonstrate that 5-MeO-DMT, when used in accordance with the present invention, has a significantly improved efficacy profile compared to approved pharmacotherapies for postpartum depression and all hallucinogens tested to date.

[0639] These data, combined with the short duration of acute hallucinogenic effects and a desirable safety profile, demonstrate that the present invention solves the technical problem of providing an improved psychoactive therapy in patients with postpartum depression.

[0640] 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 an ongoing major depressive episode.

[0641] Patients currently receiving antidepressant therapy will need to discontinue such therapy or taper off over time.

[0642] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0643] 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. 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 of treatment; 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 administration of 12 mg; and b. The 12 mg dose was safe and well tolerated.

[0644] Patients will be assessed post-injection for peak hallucinatory experience based on the patient-scored PES, sedation, and other endpoints. Follow-up visits are scheduled 1 and 7 days after the date of injecting.

[0645] 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 criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for bipolar II disorder and has an ongoing major depressive disorder 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 medication 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 administration, and have a negative serum pregnancy test at screening and a negative urine pregnancy test the day before 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.

[0646] 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 illness that, in the opinion of the study 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 been receiving 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 risk to the patient's health, 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 would cause the investigator to determine that the patient is 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 physician 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 with a DSM-5 alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

[0647] 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 an ongoing 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 an ongoing major depressive episode.

[0648] 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.

[0649] Secondary endpoints included: o Antidepressant effects of inhaled 5-MeO-DMT assessed by: The proportion of patients in remission (MADRS 10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Percent change from baseline in MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; Proportion of responders (a 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Percent change from baseline in CGI-S 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7 Percent change from baseline in the BDRS at Day 1 and Day 7. Safety and tolerability of inhaled 5-MeO-DMT, as assessed by: Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, clinical safety laboratory tests and spirometry tests; Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each dose of the study drug) and as part of the discharge assessment on Day 0; Incidence of manic or hypomanic adverse events (AEs) (assessed using DSM-5 criteria for mania / hypomania), Percent change from baseline in the YMRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Assessment of patient discharge readiness using the Clinical Assessment of Discharge Readiness (CADR) at discharge day 0; Percent change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; · C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA). The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; · PsE assessment using the PES to assess peak experience (PE) achievement (PE Scale (PES) total score ·75); ·Challenging Experience Questionnaire (CEQ), ·Mystical Experience Questionnaire (MEQ-30). · Duration of PsE, defined as the time from administration of the test 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 Day 1 and Day 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: Rapid Visual Information Processing (RVP) inspection, Verbal Recognition Memory (VRM) test, Spatial Working Memory (SWM) test, · Digit Sign Substitution Test (DSST).

[0650] Example 10 – Clinical trial of intravenous administration of 5-MeO-DMT to patients with bipolar II disorder - hypothetical example The clinical trial will enroll adult patients with bipolar II disorder and an ongoing major depressive episode.

[0651] Patients currently receiving antidepressant therapy will need to discontinue such therapy or taper off over time.

[0652] Patients will receive a daily individualized 5-MeO-DMT dosing regimen by intravenous injection. 5-MeO-DMT is provided in the form of its hydrobromide salt and a formulation for intravenous injection. It will be understood that the dosages of 5-MeO-DMT referred to below relate to the weight amount of the free base, and that dosages of the hydrobromide salt of 5-MeO-DMT can be calculated assuming that an equimolar amount is used.

[0653] More specifically, on the day of administration (day 0), patients will receive up to three doses of 5-MeO-DMT: 2 mg, 5 mg, and 8 mg. 1. All patients will receive an initial dose of 2 mg of 5-MeO-DMT. 2. The second dose (5 mg) is administered only if: a. Failure to achieve a peak experience (PES total score 75) after administration of 2 mg; and b. If the 2 mg dose was safe and well tolerated. 3. Similarly, the third dose (8 mg) is administered only if: a. Failure to achieve a peak experience (PES total score 75) after administration of 5 mg; and b. If the 5 mg dose is safe and well tolerated,

[0654] Patients will be assessed post-injection for peak hallucinatory experience based on the patient-scored PES, sedation, and other endpoints. Follow-up visits are scheduled 1 and 7 days after the date of injecting.

[0655] 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 criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for bipolar II disorder and has an ongoing major depressive disorder 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 medication 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 administration, and have a negative serum pregnancy test at screening and a negative urine pregnancy test the day before 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.

[0656] 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 illness that, in the opinion of the study 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 been receiving 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 risk to the patient's health, 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 would cause the investigator to determine that the patient is 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 physician 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 with a DSM-5 alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

[0657] The primary objective of the study is to determine the onset and durability of antidepressant efficacy of daily individualized dosing schedules of 2 mg, 5 mg, and 8 mg 5-MeO-DMT in patients with bipolar II disorder and an ongoing 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 2 mg, 5 mg, and 8 mg 5-MeO-DMT in patients with bipolar II disorder and an ongoing major depressive episode.

[0658] 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.

[0659] Secondary endpoints included: Antidepressant effects of 5-MeO-DMT administered by intravenous injection as assessed by: The proportion of patients in remission (MADRS 10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Percent change from baseline in MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; Proportion of responders (a 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Percent change from baseline in CGI-S 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7 Percent change from baseline in the BDRS at Day 1 and Day 7. Safety and tolerability of 5-MeO-DMT administered by intravenous injection, as assessed by: Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, clinical safety laboratory tests and spirometry tests; Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each dose of the study drug) and as part of the discharge assessment on Day 0; Incidence of manic or hypomanic adverse events (AEs) (assessed using DSM-5 criteria for mania / hypomania), Percent change from baseline in the YMRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Assessment of patient discharge readiness using the Clinical Assessment of Discharge Readiness (CADR) at discharge day 0; Percent change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; · C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA). The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; · PsE assessment using the PES to assess peak experience (PE) achievement (PE Scale (PES) total score ·75); ·Challenging Experience Questionnaire (CEQ), ·Mystical Experience Questionnaire (MEQ-30). · Duration of PsE, defined as the time from administration of the test 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 Day 1 and Day 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: Rapid Visual Information Processing (RVP) inspection, Verbal Recognition Memory (VRM) test, Spatial Working Memory (SWM) test, · Digit Sign Substitution Test (DSST).

[0660] Example 11 – Clinical trial of intravenous administration of 5-MeO-DMT to patients with bipolar II disorder - hypothetical example The clinical trial will enroll adult patients with bipolar II disorder and an ongoing major depressive episode.

[0661] Patients currently receiving antidepressant therapy will need to discontinue such therapy or taper off over time.

[0662] Patients will receive a daily individualized 5-MeO-DMT dosing regimen by intravenous injection. 5-MeO-DMT is provided in the form of its hydrobromide salt and a formulation for intravenous injection. It will be understood that the dosages of 5-MeO-DMT referred to below relate to the weight amount of the free base, and that dosages of the hydrobromide salt of 5-MeO-DMT can be calculated assuming that an equimolar amount is used.

[0663] More specifically, on the day of administration (day 0), patients will receive up to three doses of 5-MeO-DMT: 1 mg, 2 mg, and 3 mg. 1. All patients will receive an initial dose of 1 mg of 5-MeO-DMT. 2. The second dose (2 mg) is administered only if: a. Failure to achieve a peak experience (PES total score 75) after administration of 1 mg; and b. If the 1 mg dose is safe and well tolerated, 3. Similarly, a third dose (3 mg) is administered only if: a. Failure to achieve a peak experience (PES total score 75) after administration of 2 mg; and b. If the 2 mg dose was safe and well tolerated.

[0664] Patients will be assessed post-injection for peak hallucinatory experience based on the patient-scored PES, sedation, and other endpoints. Follow-up visits are scheduled 1 and 7 days after the date of injecting.

[0665] 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 criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) for bipolar II disorder and has an ongoing major depressive disorder 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 medication 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 administration, and have a negative serum pregnancy test at screening and a negative urine pregnancy test the day before 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.

[0666] 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 illness that, in the opinion of the study 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 been receiving 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 risk to the patient's health, 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 would cause the investigator to determine that the patient is 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 physician 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 with a DSM-5 alcohol or substance use disorder (excluding tobacco or caffeine use disorder) within 6 months prior to screening.

[0667] The primary objective of the study is to determine the onset and durability of antidepressant efficacy of daily individualized dosing schedules of 1 mg, 2 mg, and 3 mg 5-MeO-DMT in patients with bipolar II disorder and an ongoing 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 1 mg, 2 mg, and 3 mg 5-MeO-DMT in patients with bipolar II disorder and an ongoing major depressive episode.

[0668] 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.

[0669] Secondary endpoints included: Antidepressant effects of 5-MeO-DMT administered by intravenous injection as assessed by: The proportion of patients in remission (MADRS 10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Percent change from baseline in MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; Proportion of responders (a 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Percent change from baseline in CGI-S 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7 Percent change from baseline in the BDRS at Day 1 and Day 7. Safety and tolerability of 5-MeO-DMT administered by intravenous injection, as assessed by: Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, clinical safety laboratory tests and spirometry tests; Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each dose of the study drug) and as part of the discharge assessment on Day 0; Incidence of manic or hypomanic adverse events (AEs) (assessed using DSM-5 criteria for mania / hypomania), Percent change from baseline in the YMRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Assessment of patient discharge readiness using the Clinical Assessment of Discharge Readiness (CADR) at discharge day 0; Percent change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; · C-SSRS classification based on the Columbia Suicide Assessment Classification Algorithm (C-CASA). The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; · PsE assessment using the PES to assess peak experience (PE) achievement (PE Scale (PES) total score ·75); ·Challenging Experience Questionnaire (CEQ), ·Mystical Experience Questionnaire (MEQ-30). · Duration of PsE, defined as the time from administration of the test 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 Day 1 and Day 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: Rapid Visual Information Processing (RVP) inspection, Verbal Recognition Memory (VRM) test, Spatial Working Memory (SWM) test, · Digit Sign Substitution Test (DSST).

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for the treatment of psychomotor retardation in patients suffering from psychomotor retardation, which is administered intravenously, intramuscularly, or subcutaneously.

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

3. The reduction or disappearance of the 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 after, at least seven days, at least fourteen days, and / or at least twenty-eight days, according to claim 2.

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 the aforementioned 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 suffering from an ongoing 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 leads to improvement of the diagnosed disorder in a patient who also suffers from related psychomotor retardation.

11. The pharmaceutical composition according to claim 10, wherein the improvement in the diagnosed disorder in a patient also suffering from associated psychomotor retardation, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, is observed about two hours after the last dose of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last dose of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours after the last dose, 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 suffers 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 a mental or neurological disorder, such as a disorder characterized by a related psychomotor retardation and a depressive episode, e.g., major depressive disorder (MDD); bipolar disorder (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 the use of psychoactive substances, e.g., substance use disorder (SUD); psychotic disorders, e.g., schizophrenia; dementia, e.g., Alzheimer's disease (AD); Lewy body dementia (DLB); vascular dementia and Parkinson's disease type dementia; Parkinson's disease (PD); and chronic fatigue syndrome.

17. The pharmaceutical composition according to claim 16, wherein the treatment leads to improvement of psychomotor retardation and sleep disorders, and further leads to improvement of the associated mental or nervous system disorders.

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

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

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 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in 1 to 6 doses within 24 hours.

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

23. The pharmaceutical composition according to claim 22, wherein a higher dose is used in each subsequent administration than in the previous administration.

24. The pharmaceutical composition according to claim 22, wherein the patient is administered a subsequent dose unless he or she experiences a supreme hallucinatory experience.

25. The pharmaceutical composition according to claim 22, 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.

26. 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 in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (mystical, positive mood, transcendence of time and space, and inexpressibility), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving at least 75 on the Peak Experience Scale (PES) Total Score.

27. The pharmaceutical composition according to claim 1 or 2, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous injection.

28. The pharmaceutical composition according to claim 1 or 2, wherein psychomotor retardation is measured using the Salpêtrière Retardedness Rating Scale (SRRS).