5-methoxy-n, n-dimethyltryptamine for treatment of cognitive dysfunction

Abstract

5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, is useful for the treatment of a patient suffering from cognitive dysfunction wherein the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is administered via the intravenous, intramuscular or subcutaneous route.

Description

Technical Field

[0001] The present invention relates to improved methods for treating cognitive dysfunction. Cognitive dysfunction is particularly likely to occur in patients suffering from mental or neurological disorders, or medical health conditions that lead to related mental or neurological disorders. It may also occur in patients suffering from sleep disorders (e.g., insomnia).

[0002] In addition, cognitive dysfunction also occurs in the setting of unspecified neurocognitive disorder, which is defined as a disorder that presents with symptoms characteristic of a neurocognitive disorder that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning but does not meet full criteria for any etiologically relevant disorder.

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

[0004] Cognitive dysfunction refers to deficits in attention, verbal and nonverbal learning, short-term and working memory, visual and auditory processing, problem solving, processing speed, and motor function.

[0005] Cognitive dysfunction is associated with several psychiatric or neurological disorders. It also occurs in patients with certain medical health conditions, leading to related psychiatric or neurological disorders.

[0006] Cognitive dysfunction may take the form of a neurocognitive disorder, wherein cognitive dysfunction is a prominent feature of the disorder.

[0007] Furthermore, cognitive dysfunction is associated with sleep disturbances such as insomnia.

[0008] Cognitive complaints were associated with relatively lower quality of daily life, greater depression, greater anxiety, greater perceived stress, and poorer overall mental health.

[0009] Cognitive impairment requires detailed assessment and management.

[0010] Cognitive impairment is treated with both nonpharmacological approaches (using cognitive, physical, and social activities) and pharmacological approaches. Some interventions focus primarily on improving quality of life and limiting residual deficits.

[0011] Physical activity, cognitive training and exercise, proper sleep, and relaxation techniques can contribute to cognitive health. Environmental approaches, such as reducing noise around the patient, help the patient focus on the task and reduce distraction, confusion, and frustration.

[0012] In patients suffering from cognitive dysfunction associated with a psychiatric or neurological disorder, known treatments for the psychiatric or neurological disorder do not necessarily improve the cognitive dysfunction.

[0013] For example, patients with major depressive disorder (MDD) often complain of difficulty paying attention, which negatively impacts their daily functioning, and these attention problems are not alleviated by current first-line treatments. Selective serotonin reuptake inhibitors (SSRIs) are the current first-line pharmacotherapy for depression, but have generally not been shown to reduce or even eliminate cognitive dysfunction. Many studies (although primarily observational or using a combination of medications) have shown no changes in sustained attention, selective attention, or divided attention despite improvements in mood symptoms.

[0014] Similar observations have been made in the treatment of other psychiatric or neurological disorders.

[0015] Therefore, there is a need for improved methods for treating cognitive dysfunction. Summary of the invention

[0016] One object of the present invention is, in particular, to provide a therapy that is more effective than previously described therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) an earlier onset of clinical response, and / or d) a more durable clinical response).

[0017] It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, said therapies having better safety and / or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, said therapies being more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies, said therapies being associated with higher rates of patient compliance (including higher rates of treatment initiation) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that benefit from such improved psychoactive therapies.

[0018] The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients suffering from cognitive dysfunction.

[0019] The present invention also relates to 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in treating patients suffering from cognitive dysfunction, wherein the cognitive dysfunction is a defect or impairment in one or more cognitive domains selected from the group consisting of complex attention, executive function, learning and memory, language, sensorimotor function and social cognition, in particular complex attention.

[0020] Furthermore, the present invention relates to 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in treating patients suffering from cognitive dysfunction, wherein the cognitive dysfunction affects one or more subdomains of the cognitive field complex attention (the subdomains being selected from sustained attention, divided attention, selective attention and processing speed), in particular the subdomain sustained attention of the cognitive field complex attention.

[0021] According to the present invention, cognitive dysfunction is in the form of neurocognitive disorder, such as mild neurocognitive disorder or severe neurocognitive disorder.

[0022] Cognitive dysfunction may occur in patients suffering from psychiatric or neurological disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorder; obsessive-compulsive disorder (OCD) and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraine; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; Disease); dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia; Huntington's disease (HD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; or a medical health condition that results in an associated psychiatric or neurological disorder, such as cognitive impairment caused by HIV infection, traumatic brain injury, or COVID sequelae.

[0023] Patients may also suffer from sleep disturbances associated with cognitive dysfunction.

[0024] The present invention also provides dosage ranges and administration regimens that can be used to treat sleep disorders.

[0025] In the context of the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous administration.

[0026] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience. A dose of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of a pharmaceutically acceptable salt thereof may be administered. DETAILED DESCRIPTION

[0027] definition

[0028] As used in the context of the present invention, unless otherwise indicated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. Assuming that equimolar amounts are used, the appropriate weight of the salt to be administered can be calculated based on the weight of the free base.

[0029] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional in accordance with generally accepted medical practice as suffering from cognitive dysfunction or who has been diagnosed by a licensed professional in accordance with generally accepted medical practice as suffering from a psychiatric disorder or a neurological disorder associated with cognitive dysfunction. In the latter case, assessment of cognitive dysfunction may or may not be part of the diagnosis.

[0030] For example, the diagnosis of mental disorder or nervous system disorder can be carried out according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) issued by the American Psychiatric Association. In some cases, as will be apparent from the discussion of the specific circumstances below, it is possible to modify or supplement the criteria to better define a patient or patient population that is particularly benefited from treatment according to the present invention. Diagnosis will be carried out by a doctor or psychologist. It is not enough for a human subject to believe that he or she suffers from the disorder.

[0031] As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, illness or disorder, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, illness or disorder.

[0032] "Treatment of cognitive dysfunction" shall include the management and care of a patient for the purpose of combating cognitive dysfunction, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of cognitive dysfunction or to eliminate cognitive dysfunction.

[0033] Cognitive dysfunction may be related to sleep disturbances (e.g., insomnia), psychiatric or neurological disorders, or other medical conditions. Cognitive dysfunction may manifest as neurocognitive disorder.

[0034] The patient may suffer from a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. The patient has not adequately improved after at least two adequate courses of treatment, in particular, at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy. In particular, at least two prior courses of treatment were administered during the current episode of the disease, for example, if the patient suffers from a disorder characterized by a depressive episode, during the current depressive episode.

[0035] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human being that is being sought by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0036] "Clinical response" includes, but is not limited to, improvement on rating scales that assess (i) cognitive function (impairment) or aspects of cognitive function (impairment) and / or (ii) a psychiatric or neurological disorder or aspects of such disorders and / or (iii) a medical health condition that contributes to the relevant psychiatric or neurological disorder and / or (iv) sleep.

[0037] The severity of the disorder, as well as changes in severity, can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and efficacy of treatment.

[0038] The CGI rating scale was developed to provide a brief, independent assessment of the clinician's perception of a patient's global functioning before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0039] The CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is the patient currently?” Rated on a seven-point scale: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat severely ill; 6 = severely ill; and 7 = the sickest patient.

[0040] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0041] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with the condition before treatment (the so-called baseline value). Again, there is only one inquiry rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

[0042] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI). It consists of one item based on the CGI and adapted for the patient. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0043] Individual items as well as subcombinations of individual items of the scales as described herein can be used to assess specific disease aspects.

[0044] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. The active compound is administered by intravenous administration, intramuscular administration or subcutaneous administration.

[0045] As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined order of one or more separate administrations.

[0046] Cognitive dysfunction

[0047] Cognition includes the skills needed for thinking, memory, attention, and problem solving. Loss or decline in these skills can lead to cognitive impairment, a term used in this article to refer to deficits or impairments in any cognitive domain. Cognitive impairment may be a manifestation of an underlying medical condition.

[0048] The DSM-5 defines six key areas of cognitive function: complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition.

[0049] Cognitive dysfunction can affect one or more of these areas. In fact, cognitive abilities are highly correlated, and it is not uncommon for more than one area to be affected.

[0050] For example, the domain complex attention has the subdomains sustained attention (often called “concentration” or “focus”), divided attention, selective attention, and processing speed.

[0051] Therefore, complex attention clearly encompasses aspects that are critical to a variety of cognitive tasks, such as executive function as well as learning and memory. Cognitive control or executive function is essentially attention. In addition, perception and decision-making are also deeply influenced by attentional capacity.

[0052] Therefore, attention can be tested not only in isolation but also with cognitive control tasks / executive functions. If attention is impaired, other types of cognitive abilities may also be impaired. One must pay attention to stimuli before one can comprehend language, perceive visual-spatial relationships, remember information, or solve problems.

[0053] Cognitive dysfunction (the term being used herein to refer to an acquired disorder and thus representing a decline from a previously achieved level of function) can be related to a variety of processes.

[0054] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained during aging and may even improve over time. However, even in the absence of any pathological disorder, aging also leads to a decline in abilities such as abstract thinking, reasoning, and decision-making. These deteriorations are associated with potential age-related deficits in processing speed, attention, memory, and executive function that indicate cognitive aging.

[0055] In addition to normal aging, cognitive impairment may be associated with a psychiatric or neurological disorder or some other medical condition.

[0056] Mental or neurological disorders that cause or are associated with cognitive dysfunction include disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorder; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder. =Preventing post-traumatic stress disorder (PTSD); pain disorders such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia (PDD), Lewy body dementia, vascular dementia, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; psychiatric or neurological disorders related to HIV, traumatic brain injury, or COVID sequelae. Cognitive dysfunction may also occur in patients with sleep disturbances, such as insomnia.

[0057] Additionally, cognitive dysfunction occurs in disorders that present with characteristic symptoms of a neurocognitive disorder that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning but does not meet full criteria for any etiologically related disorder.

[0058] Cognitive dysfunction may manifest as neurocognitive disorders.

[0059] Mild neurocognitive disorder, also known as mild cognitive impairment, is characterized by a mild cognitive decline from previous performance levels in one or more cognitive domains. Affected patients are still able to maintain independence and complete daily tasks. However, patients' functioning is usually at a suboptimal level. Daily tasks become more strenuous as compensatory strategies are employed to maintain independence.

[0060] In severe neurocognitive impairment, a significant decline in cognitive ability from previous performance levels is observed in one or more cognitive domains. Cognitive deficits interfere with independence in daily activities.

[0061] Measuring cognitive impairment

[0062] Cognitive impairment can be assessed using questionnaires or neuropsychological assessments.

[0063] Questionnaires assess a person's mental status based on observations by the person, a caregiver, or a clinician who fills out the questionnaire. Questionnaires used to assess a person for specific mental or neurological disorders may include items related to cognitive function.

[0064] A neuropsychological assessment is a process that comprehensively evaluates a person's cognitive, psychological / emotional, and behavioral functioning. A core component of a neuropsychological assessment is the administration of neuropsychological tests to formally assess cognitive functioning.

[0065] Performance on these tests is compared to standards appropriate for the patient's age, education, and cultural background. Testing usually uses a performance-based set of questions, also called a neuropsychological battery.

[0066] The abilities tested include language processing, visuospatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory perceptual function.

[0067] Common tests for assessing cognitive impairment include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and the Mini-Cog TM , Screening for Cognitive Impairment in Psychiatry (SCIP) and MATRICS Consensus Cognitive Battery (MCCB).

[0068] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses different cognitive domains: short-term memory; visuospatial abilities; executive functions; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30, with 26 or more being normal, 18-25 being mild cognitive impairment, 10-17 being moderate cognitive impairment, and less than 10 being severe cognitive impairment.

[0069] The Mini-Mental State Examination (MMSE) is an 11-question measurement tool that tests five areas of cognitive function: orientation, recording, attention and calculation, recall, and language. The maximum score is 30. The original score may also need to be modified based on education and age.

[0070] Four cut-off levels were used to classify the severity of cognitive impairment: 24-30 means no cognitive impairment; 19-23 means mild cognitive impairment; 10-18 means moderate cognitive impairment; and ≤9 means severe cognitive impairment.

[0071] Used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

[0072] Mini-Cog TMThe Cognitive Impairment Test is a short screening questionnaire for cognitive impairment. It combines a 3-word recall test with a clock drawing test. The clock drawing test assesses a number of cognitive areas that may be affected, such as executive function, visuospatial abilities, motor programming, and attention. After taking the clock drawing test, one point is awarded for each three words correctly recalled; a correct drawing of a clock is worth two points. A score < 4 indicates cognitive impairment.

[0073] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening tool that examines cognitive performance in patients with psychiatric disorders.

[0074] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), the Working Memory Test (WMT), the Verbal Fluency Test (VFT), the Verbal Learning Test-Delayed (VLT-D), and the Processing Speed ​​Test (PST). There are three different test formats to facilitate repeated testing, which can reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score below 70 indicates cognitive impairment.

[0075] Cognitive dysfunction may also be assessed using the MCCB (MATRICS Consensus Cognitive Battery) or one or more of its different subtests. These subtests include: Trail Making Test Part A (tests processing speed); Brief Assessment of Cognitive Abilities in Schizophrenia, Symbol Coding Subtest (processing speed); Hopkins Verbal Learning Test-Revised, Immediate Recall, Three Learning Trials Only (verbal learning); Wechsler Memory Scale-3rd Edition, Spatial Span Subtest (working memory (nonverbal)); Letter-Digit Span Test (working memory (verbal)); Neuropsychological Assessment Battery, Maze Subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category Fluency Test, Animal Naming (processing speed); Mayer-Salovey-Caruso Emotional Quotient Test, Managing Emotions Branch (social cognition); and Sustained Performance Test, Same Paired Version (attention / vigilance).

[0076] The test battery is suitable for measuring cognitive changes.

[0077] Further testing included the verbal recognition memory (VRM) test, the rapid visual information processing (RVP) test, the spatial working memory (SWM) test, and the digit symbol substitution test (DSST).

[0078] Scales for the assessment of mental and neurological disorders

[0079] A variety of scales have been proposed to assess the severity of psychiatric or neurological disorders.Such scales are based on tests that can be self-administered or administered by a clinician.

[0080] Scales for assessing mental or neurological disorders that can be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring mental or neurological disorders as discussed in more detail below.

[0081] Treatment outcomes are assessed by using one or more indices or scales at one or more time points after completion of the course of treatment.

[0082] The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2 to 3 hours after the last administration. Early assessment can generally be performed, for example, about 2 hours or about 3 hours after the last administration.

[0083] However, assessment of the effects on sleep disturbance can be performed as early as the day after treatment (ie, day 1), allowing treated patients the opportunity to get at least one night of sleep.

[0084] Thus, an assessment on day 1 or day 1 means an assessment on the second day after administration. The assessment will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. The assessment may be performed after about 24 hours.

[0085] Assessment on or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

[0086] When clinical response is assessed at an early time point (e.g., 2 hours) after drug administration, for example, when one of the scales is used to assess the severity of a psychiatric or neurological disorder, such endpoints may be reasonably modified based on endpoints developed for longer recall periods (e.g., MADRS is typically 7 days) (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration). This also applies to any other scale used herein, unless a recall period is specifically specified.

[0087] The considerations outlined apply to early time points because, on the one hand, in order to assess clinical response, the influence of the patient's pre-treatment status on any scores recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0088] At a later time point, such as on day 1 or later, all items of the relevant scales used to assess clinical response can generally be assessed, using an appropriate recall period (if necessary), so that no pre-treatment scores need to be carried forward.

[0089] Potential mechanisms of cognitive impairment

[0090] Brain processes can be studied by functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0091] Functional images of the brain are acquired over several minutes. Low-frequency BOLD signal oscillation patterns are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and inversely correlated fluctuations.

[0092] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0093] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0094] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks are characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0095] RSNs have been shown to be responsible for various aspects of complex brain function, and these networks of connectivity have been found to be impaired in various disease states. Such disease states, including certain forms of cognitive dysfunction, are associated with altered functional connectivity within a specific resting-state network and / or between one or more regions in one or more additional resting-state networks.

[0096] Resting-state fMRI is particularly advantageous when studying groups affected by cognitive dysfunction because it enables the examination of functional connectivity while removing task demands that may be confounded by underlying cognitive or motor impairments.

[0097] Cognitive processes are reflected by the functional connectivity of certain brain regions within and / or between regions located in different networks.

[0098] Specifically, certain core networks, also called “higher-order cognitive networks,” appear to be critical for most mental activities.

[0099] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), the central executive network (CEN), or the executive network (EN), is often associated with executive functions. These functions include holding and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decision-making and goal-directed behavior.

[0100] Another core network is the default mode network (DMN). The DMN contains regions in the brain that are most active when an individual's attention is not focused on any specific task. Activity in the DMN is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, integration of cognitive and emotional processing, and free thoughts unrelated to the task.

[0101] The third network is the salience network, also known as the cingulo-opercular network. This network is involved in identifying salient stimuli and events, that is, stimuli and events that other brain networks need to pay attention to. This network plays a central role in controlling mental processes and behavior.

[0102] The fourth network is the dorsal attention network (DAN). The DAN is associated with top-down, goal-directed attention processes.

[0103] The above networks do not operate independently. In fact, there are countless connections between them. Cooperation between networks is essential for the functioning of specific tasks.

[0104] Brain networks undergo functional reorganization throughout the lifespan, with concurrent effects on cognition. During healthy aging, age-related alterations are observed in higher-order cognitive networks.

[0105] Patients with cognitive impairment showed altered functional connectivity within and / or between resting-state networks compared to age-matched healthy controls. Alterations were observed within and / or between the default mode network, executive network, salience network, and dorsal attention network.

[0106] In many instances, resting-state networks are involved in cognition, which is affected by psychiatric or neurological disorders, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, for example, separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder and phobias, and substance / medication-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, for example, obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); somatoform disorders, for example, body dysmorphic disorder (BDD); obsessive-compulsive disorder (OCD); and body dysmorphic disorder (BDD). CD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain and fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia (PDD), Lewy body dementia, vascular dementia, frontotemporal dementia; Parkinson's disease (PD); Huntington's disease (HD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; psychiatric or neurological disorders related to HIV, traumatic brain injury, or COVID sequelae.

[0107] Resting-state networks involved in cognition can also be affected by psychiatric or neurological disorders, as a result of certain medical health conditions, and unspecified neurocognitive disorders.

[0108] Furthermore, resting-state networks involved in cognition are affected by sleep disturbances such as insomnia. In fact, cognitive dysfunction and sleep impairment are associated.

[0109] Patients with disturbed sleep have worse cognitive function, and patients with cognitive impairment often also have impaired sleep.

[0110] Active Agent

[0111] The above discussion shows that cognitive impairment is characterized by several aspects that themselves carry a significant disease burden and should be appropriately treated.

[0112] The inventors believe that carefully selected hallucinogens may lead to treatments that improve important aspects of cognitive dysfunction and may lead to overall improvement of the disorder.

[0113] A group of hallucinogens consists of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often called "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

[0114] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, of which the indoleamines are divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

[0115] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-associated receptors.

[0116] Recently published studies using serotonergic psychedelics such as LSD, psilocybin, and DMT (using the shamanic medicine ayahuasca containing DMT) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may hamper their clinical use.

[0117] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138 (11): 1508-9) reported a patient who had a manic episode after taking LSD or LSD analogs. The patient had symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23 (4): 1-3) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP and Jose MSmith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a man with bipolar disorder who switched to mania after consuming ayahuasca, a beverage containing DMT.

[0118] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49 (4), 294-296.

[0119] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

[0120] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for use in therapy. 5-MeO-DMT has unique pharmacological properties that are distinct from other psychedelic compounds.

[0121] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype than other classic psychedelics.

[0122] As further detailed in the Examples section below, the inhibition constants (K) for psilocin (the dephosphorylated form of psilocybin formed following ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin dephosphate, DMT, and 5-MeO-DMT at the 5-HT2A receptor in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while dephosphopsilin and DMT exhibit moderate affinity. i values) were 37, 117, and 122 nM, respectively. Thus, dephosphorylated psilocybin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0123] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

[0124] 5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0125] Compared to other psychedelics (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing a significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

[0126] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0127] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

[0128] Further, it has been reported that antidepressants induce isolated hypomanic episodes in patients suffering from treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of inducing hypomania.

[0129] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to, for example, several hours with oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0130] In addition, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [ 3 H]LSD and serotonin to estimate nonspecific binding and determine K i It is 2.3nM.

[0131] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0132] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0133] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0134] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0135] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0136] The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders and / or cognitive dysfunction.

[0137] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social / emotional withdrawal. This is supported by the clinical results shown in the studies mentioned herein.

[0138] Another characteristic of 5-MeO-DMT is its short half-life.

[0139] 5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0140] The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0141] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0142] The properties of 5-MeO-DMT make the compound particularly suitable for treating cognitive dysfunction, particularly in patients suffering from psychiatric or neurological disorders, or medical health conditions that lead to related psychiatric or neurological disorders; patients suffering from sleep disorders (e.g., insomnia); patients suffering from unspecified neurocognitive disorders.

[0143] The properties of 5-MeO-DMT also allow for specific dosing regimens, as discussed in more detail below.

[0144] According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used.When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0145] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0146] A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

[0147] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0148] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

[0149] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

[0150] Methods for the preparation of these compounds are known in the art.

[0151] Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0152] Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

[0153] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

[0154] In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0155] An example of a suitable organic moiety is C(O)OR 1 、-C(O)R 2 、-CH(R 3 )OR 4 、-C(O)OCH(R 3 )OC(O)R 4 、-C(O)OCH(R 3 )OC(O)OR 4 、-CH(R 3 )C(O)R 4 、-CH(R 3 )OC(O)R 4 、-CH(R 3 )OC(O)OR 4 , where R 1 , R 2 , R 3 and R 4 Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

[0156] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 , R 3 and R 4 As defined above.

[0157] Prodrugs, especially prodrugs of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0158] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0159] Methods for preparing prodrugs as discussed herein are known in the art.

[0160] According to the present invention, the T of the metabolite 5-MeO-DMT measured after oral administration of the prodrug at 10 mg / kg in male Sprague-Dawley (SD) rats max The value is preferably 1 hour or less, more preferably 0.7 hour or less, particularly 0.5 hour or less.

[0161] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0162] Mode of administration

[0163] Therapeutically effective amounts of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., administration by intravenous injection.

[0164] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration via injection, and examples of excipients and vehicles for such formulations are known in the art.

[0165] Dosage regimen

[0166] The present invention also provides dosage ranges, specific dosages and dosing regimens (administration regimens) and appropriate administration routes.

[0167] The present invention is based in part on the inventors' conclusion that the peak psychedelic experience occurs during the acute phase following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which drives the therapeutic benefit of 5-MeO-DMT or a pharmaceutically acceptable salt thereof in patients suffering from cognitive dysfunction, particularly one or more aspects as defined above, either causally or at least as a surrogate behavioral marker of a potential unknown therapeutic mechanism.

[0168] Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility in individual patients will result in a better therapeutic profile than previously tested psychedelics, dosing regimens, and routes of administration.

[0169] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0170] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be achieved with other psychedelics due to the late onset and prolonged duration of the psychedelic effects and due to the rapid development of tolerance (i.e., the psychedelic effects diminish or disappear upon re-administration), which may persist for several days.

[0171] A patient suffering from cognitive dysfunction as defined herein is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0172] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other treatment for cognitive dysfunction.

[0173] The dosage range of 5-MeO-DMT administered to a patient suffering from cognitive dysfunction as defined herein is from about 1 mg to about 10 mg, or any range therein, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated based on the specified weight of 5-MeO-DMT free base assuming the use of equimolar amounts. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Please note that in this specification, when a range is listed (such as "about 1 mg to about 10 mg"), the inventors consider all discrete values ​​within the range, some of which are explicitly mentioned, but not all of them - this is only for the purpose of brevity.

[0174] In a preferred embodiment, the improved method of treating a patient suffering from cognitive dysfunction as defined herein using a therapeutically effective amount of 5-MeO-DMT comprises a clinical response occurring no later than about 2 hours after administration of the 5-MeO-DMT.

[0175] In preferred embodiments, improved methods of treating patients suffering from cognitive dysfunction as defined herein with a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0176] In a preferred embodiment, the improved method of treating a patient suffering from cognitive dysfunction as defined herein with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0177] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0178] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0179] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0180] In embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0181] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until reaching 10 mg, or all administrations within that treatment block have been administered, whichever is earlier.

[0182] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

[0183] For embodiments in which the dose of a subsequent administration is increased, the dose of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dose of the previous administration. For example, if the first administration was 1 mg and the dose increase is 3 mg, the second administration is 4 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administration is 7 mg.

[0184] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg at the first administration, and then increased to a dose selected from about 4 mg to about 6 mg at the second administration, and to a dose selected from about 7 mg to about 9 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0185] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg at the first administration, and then increased to a dose selected from about 1.5 mg to about 2.5 mg at the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0186] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 8 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 8 mg.

[0187] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 1 mg to about 3 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration in the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0188] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 0.5 mg to about 1.5 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 1.5 mg to about 2.5 mg, and the third administration in the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0189] It will be appreciated that a pharmaceutically acceptable salt of 5-MeO-DMT is preferred for all of the above dosing regimens and that, assuming equimolar amounts are used, the appropriate weight of salt to be administered can be calculated based on the specified weight of the free base.

[0190] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0191] Patients can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0192] Whether a patient has a “peak psychedelic experience” can also be determined by achieving at least 60% of the maximum possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0193] According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 to the following three questions: 1. How intense was the experience; 2. How much loss of control was there; 3. How significant (i.e., profound and important) was the experience?

[0194] Treatment of cognitive impairment

[0195] According to the present invention, cognitive dysfunction occurring in patients suffering from mental disorders or neurological disorders or medical health disorders leading to related mental or neurological disorders can be treated. In addition, cognitive dysfunction occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

[0196] Cognitive dysfunction in unspecified neurocognitive disorders may also be treated.

[0197] In a patient suffering from cognitive dysfunction associated with another disorder as detailed above, treatment of cognitive dysfunction according to the invention results in an improvement of the disorder associated with cognitive dysfunction.

[0198] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0199] Administration of 5-MeO-DMT 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 rewire. New, healthy functional connections are established, and this has lasting effects.

[0200] Thus, according to the present invention, affecting these networks through therapies as described herein will result in improvements in cognitive dysfunction and, if the patient being treated suffers from a psychiatric or neurological disorder, will also result in improvements in that disorder; if the patient being treated suffers from a medical health disorder that causes the relevant psychiatric or neurological disorder, will also result in improvements in the relevant psychiatric or neurological disorder; if the patient being treated suffers from a sleep disorder (e.g., insomnia), will also result in improvements in the sleep disorder (e.g., insomnia); if the patient suffers from an unspecified neurocognitive disorder, will also result in improvements in one or more other symptoms of the disorder.

[0201] To further support the clinical utility of 5-MeO-DMT in patients suffering from cognitive dysfunction, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in cognitive dysfunction, which is also commonly observed in patients suffering from other disorders.

[0202] The data are derived from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). Although TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for other disorders associated with cognitive dysfunction.

[0203] In clinical trials, 5-MeO-DMT was administered via 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 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

[0204] The data collected included assessments of the treated patients for several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as items related to cognitive dysfunction) were associated with other disorders, in which cognitive dysfunction was based on similarly altered functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0205] Multiple patients in the recruited cohort showed significant improvements, and this result confirms the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0206] More specifically, one aspect that can be treated by administering 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT can be administered to a patient to reduce or eliminate cognitive dysfunction, particularly difficulty concentrating, in the patient.

[0207] The MADRS item that is particularly relevant to impaired concentration and memory is "difficulty concentrating." This item represents difficulty collecting one's thoughts, resulting in an inability to concentrate, and is scored on a scale of 0 to 6. If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty collecting one's thoughts, the score is 2. If there is difficulty concentrating and maintaining thoughts, resulting in reduced ability to read or have a conversation, the score is 4. If the patient cannot read or talk easily, the score is 6.

[0208] In the study group that received the individualized dosing regimen, all eight patients had a total score of 30 for the MADRS item “difficulty concentrating” at baseline.

[0209] After 2 hours, the score dropped to 11, which corresponds to 19 points or 63% improvement. On the first day after treatment, the score dropped to 1, which corresponds to 29 points or 97% improvement. On the seventh day after treatment, the score dropped to 9, which corresponds to 21 points or 70% improvement.

[0210] In the 12 mg group, the total score for the MADRS item “difficulty concentrating” was 16 at baseline for all four patients.

[0211] After 2 hours, the score dropped to 7, which corresponds to 9 points or 56% improvement. On the first day after treatment, the score dropped to 2, which corresponds to 14 points or 88% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to 13 points or 81% improvement.

[0212] Thus, according to the present invention, treating a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction.

[0213] More specifically, according to the present invention, treatment of a patient with 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cognitive dysfunction, reduces or eliminates the cognitive dysfunction, wherein the cognitive dysfunction is a defect or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition. For example, if the cognitive dysfunction affects the cognitive domain complex attention, such as one or more subdomains of the cognitive domain complex attention (selected from sustained attention, divided attention, selective attention, and processing speed), in particular sustained attention, the cognitive dysfunction is reduced or eliminated.

[0214] Treatment of cognitive dysfunction and sleep disturbances

[0215] Sleep disturbances are conditions that affect the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition (e.g., a psychiatric or neurological disorder, or a medical health condition that results in a related psychiatric or neurological disorder). Sleep disturbances can affect a person's ability to function normally while awake, particularly impairing cognitive function.

[0216] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depth of sleep. Non-REM and REM sleep alternate during the four to five cycles of normal human sleep each night. During the early part of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, especially in the first sleep cycle. As the night progresses, non-REM sleep becomes lighter, and more of each cycle is allocated to REM sleep.

[0217] Normal, healthy sleep consists of the different stages described above, which proceed in a continuous, strictly controlled sequence throughout the night.

[0218] Disruptions in this tight control can lead to sleep disturbances.

[0219] Common forms of sleep disturbances include disorders of falling asleep and maintaining sleep (insomnias), disorders of excessive sleepiness (hypersomnias), disorders of the sleep-wake schedule (circadian rhythm disorders), disorders related to sleep, sleep stages, or partial arousals (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0220] Insomnia is a sleep disorder in which the patient has difficulty falling asleep or staying asleep. People with insomnia have trouble falling asleep; wake up frequently during the night and have difficulty falling asleep again; wake up too early in the morning; have poor sleep quality; and / or have at least one daytime problem due to poor sleep quality, such as fatigue, sleepiness, mood problems, difficulty concentrating, accidents at work or while driving, etc.

[0221] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomniacs. Transitioning from sleep to wakefulness is difficult. Individuals who experience sleep drunkenness report being confused, disoriented, sluggish, and falling asleep again and again upon awakening.

[0222] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances due to alterations in an individual's internal circadian rhythm or due to inconsistencies between their circadian rhythm and their desired or required work or social schedules. This desynchronization may be temporary or persistent. The ensuing clinical presentation combines symptoms of insomnia and hypersomnia. Sleep duration is often shortened and interrupted, performance in the desired wakefulness state is impaired, and restoration of a normal sleep schedule is temporarily impossible.

[0223] Parasomnias refer to various forms of sleep disorders characterized by people experiencing unusual behaviors or physiological activities (such as sleepwalking or nightmares) before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias may impair sleep quality.

[0224] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of the respiratory muscles and the control center in the brain. One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals to control breathing, for example, depending on an underlying health condition. Central sleep apnea has potentially serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow leads to intermittent hypoxia, which causes sleep fragmentation due to micro-arousals or awakenings. The consequence can be excessive daytime sleepiness.

[0225] In sleep-related movement disorders, repetitive, relatively simple, often stereotyped movements disrupt sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0226] Insufficient sleep duration or quality may lead to personality changes and may not only exacerbate existing psychiatric disorders, but may also serve as a predisposing factor for their development. Sleep disturbances may also interfere with cognitive function and lead to memory impairment. Sleep-deprived subjects may experience difficulty in decision-making, irritability, poor performance, and may have slower reaction times. A recent 2019 systematic review and meta-analysis examined the relationship between insomnia and cognitive dysfunction and found significant associations with impairments in memory, complex attention, vigilance, and executive function. Insufficient sleep can also adversely affect life by contributing to the development of obesity, diabetes, and heart disease.

[0227] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatment may involve medication or psychotherapy.

[0228] Available treatments are not successful in all patients, may be associated with side effects and / or require long-term treatment to achieve a relevant therapeutic effect.

[0229] In patients suffering from sleep disturbances associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorders do not necessarily improve the sleep disturbances.

[0230] For example, sleep disturbances are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily lead to improvement in the accompanying sleep disturbances. Although most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while others may cause sleep impairment.

[0231] To assess sleep, parameters such as sleep duration, sleep architecture, sleep latency, and frequency and duration of wakefulness throughout the night can be measured. Quantitative indicators can be measured using objective methods, including polysomnography, actigraphy, and determination of sleep latency, or by self-report measurements (questionnaires).

[0232] Polysomnography is a technique that requires patients to be monitored throughout the night in a specialist clinic. Various functions are measured throughout the night, including eye movements, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body posture and movement, snoring and heart rate.

[0233] Another quantitative measurement is actigraphy. Actigraphy sensors are worn to measure motor activity, which is continuously recorded and used to assess sleep-wake cycles. This technology allows patients to continue their normal lives while recording the required data in a natural sleep environment.

[0234] Sleep latency can be measured using the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep after multiple test naps. An average sleep latency of approximately 10 minutes is considered normal; less than 8 minutes indicates sleep disturbance / excessive daytime sleepiness. An accompanying analysis of brain activity can help further diagnose a sleep disorder.

[0235] Sleep assessment questionnaires record ratings of components of sleep quality, such as perception of sleep depth, difficulty in waking, and rest after sleep, as well as other factors that may affect sleep quality, such as comorbidities and medication use. Cognitive dysfunction is often part of the assessment because it is associated with sleep disturbances.

[0236] Assessment of qualitative aspects of the sleep experience is important because sleep discomfort may often persist despite normal values ​​on quantitative sleep measures.

[0237] Questionnaires not only facilitate rapid and accurate assessment of complex clinical problems but may also be useful for tracking the patient's progress. Therefore, self-reported sleep questionnaires completed by patients are an important basis for the assessment of sleep disturbances in clinical practice.

[0238] A variety of sleep quality indices are known. The following indices include examples of questionnaires for assessing general sleep and examples of questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders and parasomnias, respectively. However, the present invention is not limited to the use of a particular index or questionnaire.

[0239] Some questionnaires rely on a recall period (recall window) of several days or even weeks. While this may be suitable for diagnosing sleep disorders, it is not always suitable for assessing the effectiveness of treatments, especially those that start quickly after treatment. For several questionnaires, the recall period can be modified so that the scores obtained reflect a period of time after treatment. In particular, this article discusses questionnaires for assessing the effects of treatment on sleep in patients suffering from specific conditions, which rely on a recall period that starts no earlier than the time point when the acute psychedelic experience subsides after the last administration. In order to meet this criterion, the normally applied recall period is modified if necessary.

[0240] For example, general sleep quality can be assessed using the Sleep Quality Scale (SQS) and the Sleep-50 questionnaire.

[0241] The Sleep Quality Scale (SQS) is an all-encompassing assessment tool that implements a universal, efficient measurement of sleep quality suitable for evaluating a variety of patients and research populations. Individual questions about daytime symptoms, such as attention problems, difficulty concentrating or memory problems (item 15 "poor sleep quality makes it difficult for me to think", item 19 "poor sleep quality causes me to make mistakes at work", item 21 "poor sleep quality makes it easier for me to forget things", item 22 "poor sleep quality causes difficulty concentrating at work"), recovery after sleep, problems falling asleep and maintaining sleep, difficulty waking up, and sleep satisfaction can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more severe sleep problems (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science + Business Media, LLC 2012). Respondents are asked to report their experiences in the last month or another appropriate recall window.

[0242] A decrease in the score indicates successful treatment.

[0243] 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 discomforts associated with sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorders, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily function. For each item, the respondent is given a scale from 1 ("not at all") to 4 ("very much") and is asked to indicate the extent to which the statement matches their experience in the last month or another appropriate recall window.

[0244] To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the respondent must also achieve a cutoff point of at least 3 or 4 ("quite a bit" or "very much", respectively) on a subscale assessing the impact of sleep discomfort on daily functioning (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005; 3(4):227-46).

[0245] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0246] A commonly used questionnaire to assess sleep disturbance is the Pittsburgh Sleep Quality Index. Other tools are the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System (PRIME). )Sleep disorders.

[0247] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-rating questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

[0248] Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. The 19 items are divided into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

[0249] Each component is scored from 0 to 3. Higher scores indicate more severe sleep disturbance. A detailed scoring description of the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213.

[0250] The seven component scores are then summed to create an overall score ranging from 0-21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas, or moderate difficulty in more than three areas.

[0251] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

[0252] The Insomnia Severity Index (ISI) is a brief questionnaire that addresses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the degree of interference of insomnia with daily functioning (Item 3, "To what extent do you think your sleep problems interfere with your daily functioning (e.g., daytime fatigue, functioning at work / daily chores, concentration, memory, mood, etc.)."), how significant the respondent feels their insomnia is compared to other people, and the level of overall distress caused by sleep problems. Individual responses can be scored from 0 (=none) to 4 (=very); higher total scores correspond to more severe insomnia. A total score of 0-7 means "no clinically significant insomnia", 8-14 means "subthreshold insomnia", 15-21 means "clinical insomnia (moderate severity)", and 22-28 means "clinical insomnia (moderate)" (A. Shahid et al., supra). The usual recall window for the ISI is two weeks, but other appropriate recall windows can also be used herein.

[0253] Treatment success is indicated by (i) a decrease in the score, for example a decrease of >7 points, particularly >8 points; preferably (ii) a decrease in the score to below the cut-off value for clinically significant insomnia.

[0254] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ rates restlessness / agitation, mental overactivity, consequences of insomnia, and lack of sleep preparation, with a particular focus on beliefs about the root causes of sleep problems. Respondents use a five-point scale to indicate how often certain statements about insomnia represent their experience. 1 means "never true," and 5 means "often true." Higher scores indicate more abnormal beliefs about the causes and associated factors of insomnia (A. Shahid et al., supra).

[0255] A decrease in the score indicates successful treatment.

[0256] Patient Reported Outcomes Information System The Sleep Disturbance Tool is a general method for assessing sleep disturbances. The tool has one long form and four different short forms (e.g., 4, 6, and 8 items) and assesses self-reported sleep quality, perception of sleep depth, and any perceived difficulties related to falling asleep and staying asleep over a 7-day period.

[0257] Each item in the measure is rated on a 5-point scale. The raw scores of each item are summed to obtain a total raw score. The total raw score is then converted to a standardized T score using a conversion table.

[0258] Treatment success was indicated by a decrease in T score.

[0259] Excessive sleeping or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0260] The Epworth Sleepiness Scale (ESS) evaluates overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, which represent moments of relative inactivity, such as an afternoon nap or sitting in a car stopped in traffic. Respondents rate their likelihood of falling asleep using a scale of 0-3 (0 means "never doze off," and 3 means "very likely doze off"). The scoring range is 0-24; the higher the score, the higher the severity of daytime sleepiness. A cutoff score of 10 indicates that daytime sleepiness may occur at a clinical level (A. Shahid et al., supra).

[0261] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 10 or less.

[0262] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses the degree of sleepiness at a particular moment. The scale consists of only one item, asking the respondent to select one of seven statements that best represents their current perceived level of sleepiness. The degree of sleepiness is assessed using a scale from 1 (=feeling active and energetic; alert; fully awake) to 7 (=almost in a trance; falling asleep quickly; unable to stay awake) (A. Shahid et al., supra).

[0263] A decrease in the score indicates successful treatment.

[0264] Parasomnias can be assessed using the Paris Arousal Disorders Severity Scale (PADSS).

[0265] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnias, assesses their frequency, and includes an evaluation of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0266] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0267] A commonly used questionnaire for the assessment of sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period may also be selected.

[0268] A decrease in the score indicates successful treatment.

[0269] The commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire requires respondents to use Likert-type ratings to indicate how severe the impact of this disorder was on them in the past week. The questions can be divided into two categories: disorder symptoms (nature, intensity and frequency) and their impact (sleep problems, daily functional disorders and resulting mood changes). Each of the ten questions requires respondents to rate their RLS experience on a scale of 0 to 4, with 4 representing the most severe and most frequent symptoms and 0 representing the least symptoms. The total score range can be 0 to 40. As a short scale with excellent psychometric quality, the tool can be applied to a variety of research and clinical purposes, including screening and evaluating treatment outcomes. (A. Shahid et al., supra).

[0270] The response to treatment can be assessed by a decrease in the score.

[0271] The treatment response can be evaluated by the above-mentioned quantitative measurements (such as polysomnography or wrist actigraphy) and / or using the above-mentioned questionnaires. A significant decrease or increase in the total score, or a significant decrease in the prevalence, frequency and impact on daily functioning, respectively, according to the corresponding sleep scale, indicates a treatment-induced improvement in sleep disturbances.

[0272] Cognitive dysfunction in insomnia is assessed as part of a sleep rating questionnaire (eg, SQS or ISI) as discussed above.

[0273] Common tests that can be used to assess cognitive impairment are the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB).

[0274] Resting-state fMRI has been widely used in patients with sleep disorders to enhance the understanding of pathophysiology and potential compensatory mechanisms.

[0275] Alterations in resting-state networks have been found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0276] In patients with insomnia, functional connectivity impairments were observed within the default mode network (DMN) and within the salience network, which are associated with the detection and integration of emotional and sensory stimuli. Studies have shown that these networks contain key areas for the integration of emotional and physical states, and that functional connectivity impairments within and / or between these networks and other brain regions may account for patients' alertness, subjective distress, and poor sleep continuity.

[0277] 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 brain functional connectivity changes somewhat resemble the vulnerability patterns seen in patients with Alzheimer's disease.

[0278] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, different DMN hubs (precuneus and medial prefrontal cortex) show significant changes, and functional connectivity in the DMN is associated with self-reported severity of sleepiness.

[0279] A study investigating differences between night-shift nurses and day-shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, involved in sleep regulation and cognitive functions such as responsiveness and alertness. In addition, functional connectivity of the DMN is fundamentally different in early and late circadian rhythm phenotypes. As with other forms of sleep disturbance, circadian rhythm disturbances can lead to changes in brain functional connectivity. Changes in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disturbances.

[0280] Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders representative of non-REM parasomnias.

[0281] The precuneus is involved in the analysis and integration of visual, auditory and somatosensory information and the monitoring of movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnias, the default mode network is affected.

[0282] Resting-state fMRI studies of patients with sleep-related breathing disorders, such as central sleep apnea, have demonstrated profound global and regional connectivity deficits, particularly in the default mode network (DMN) and in regions involved in arousal and sensorimotor systems. Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in prefrontal motor control pathways, a subregion of the default mode network. In addition, activity in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem, can be observed.

[0283] In many cases, the resting state networks involved in sleep regulation are also involved in cognition. Therefore, according to the invention, influencing these networks by the therapy according to the invention will lead to an improvement in sleep disturbances and, if the patient being treated suffers from cognitive dysfunction, also to an improvement in cognitive dysfunction.

[0284] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) demonstrate that sleep disturbances can be successfully treated by administering 5-MeO-DMT.

[0285] In the TRD study described in more detail in the Examples section below, the MADRS item "Sleep reduction" reflecting insomnia was assessed, among others.

[0286] The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the normal pattern of the subject's own health. When the subject's sleep is normal, the score is 0. A score of 2 reflects mild difficulty falling asleep, or slightly reduced, shallow or intermittent sleep time. A score of 4 means that sleep time is reduced or interrupted by at least two hours. A score of 6 means less than two or three hours of sleep.

[0287] In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

[0288] In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0289] Thus, the score of the scale item "sleep loss" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance, especially in patients suffering from psychiatric disorders or nervous system disorders.

[0290] Treatment of patients suffering from sleep disorders (particularly insomnia) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates cognitive dysfunction and leads to improvement of sleep disorders (particularly insomnia).

[0291] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0292] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0293] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected at least in improvements in scores on items 15, 19, 21 and / or 22 of the Sleep Quality Scale (SQS) on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point.

[0294] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of SQS Items 15, 19, 21 and / or 22) in patients suffering from sleep disorders (particularly insomnia) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point of the resolution of the acute psychedelic experience after the last administration to the assessment time point. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of SQS Items 15, 19, 21 and / or 22) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point of the resolution of the acute psychedelic experience after the last administration to the assessment time point.

[0295] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected at least in an improvement in the score on Item 3 of the Insomnia Severity Index (ISI) on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point.

[0296] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of item 3 of the ISI) in patients suffering from sleep disorders (particularly insomnia) occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of item 3 of the ISI) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience subsides after the last administration to the assessment time point.

[0297] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected in an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the first day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day and / or on the 28th day.

[0298] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders (particularly insomnia) (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders (particularly insomnia) (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0299] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected in an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the first day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0300] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders (particularly insomnia) (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders (particularly insomnia) (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0301] As mentioned above, cognitive dysfunction is an important aspect of patients suffering from sleep disorders. Therefore, improvement of cognitive dysfunction will also lead to improvement of sleep disorders. Since cognitive dysfunction also affects other aspects of sleep disorders, the inventors conclude that the observed improvement of cognitive dysfunction will further contribute to the overall improvement of sleep disorders (particularly insomnia).

[0302] In the case of idiopathic sleep disorders, the clinical response may be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and / or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and / or to 0 points.

[0303] Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0304] Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0305] The improvement of idiopathic sleep disturbance (reflected by a decrease in CGI-S score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0306] In the case of idiopathic sleep disorders, improvement in the sleep disorder (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0307] In the case of idiopathic sleep disorders, the improvement of the sleep disorder (at least reflected by a decrease in the score of "much improved" in the CGI-I score or the PGI-I score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0308] Improvement in sleep disturbance may also be assessed by any other scale reflecting changes in sleep quality or quantity as described above, such as the Pittsburgh Sleep Quality Index (PSQI).

[0309] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

[0310] Improvement in sleep disturbances (reflected by a decrease in PSQI scores, particularly to 5 or below) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point after the last administration when the acute psychedelic experience subsides to the assessment time point.

[0311] The improvement in sleep disturbance (reflected by a decrease in PSQI score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point.

[0312] Improvements in sleep disturbances (reflected by a decrease in PSQI scores) are observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the start time of the recall period is no earlier than the time point at which the acute psychedelic experience resolves after the last administration to the assessment time point.

[0313] Cognitive dysfunction and sleep disturbance (especially insomnia) are closely related to mental and nervous system disorders. Both cognitive dysfunction and sleep disturbance (especially insomnia) occur in mental or nervous system disorders, such as disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD) and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder and phobia and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); somatoform disorders, such as body dysmorphic disorder (BDD); obsessive-compulsive disorder ; post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain and fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia (PDD), Lewy body dementia, vascular dementia, frontotemporal dementia; Parkinson's disease (PD); Huntington's disease (HD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; psychiatric or neurological disorders related to HIV, traumatic brain injury, or COVID sequelae.

[0314] Cognitive dysfunction and sleep disturbances (particularly insomnia) also occur in medical health conditions leading to associated psychiatric or neurological disorders, HIV, traumatic brain injury, or COVID sequelae; as well as unspecified neurocognitive dysfunction.

[0315] Treatment according to the invention will result in improvement of cognitive dysfunction and sleep disturbances, in particular insomnia, and related psychiatric or neurological disorders, examples of which are listed above, and also in improvement of psychiatric or neurological disorders associated with certain medical health conditions as explained above and in improvement of unspecified neurocognitive dysfunction.

[0316] Treatment of cognitive impairment and psychiatric and neurological disorders

[0317] In patients suffering from cognitive dysfunction associated with a psychiatric disorder or a nervous system disorder, treatment of cognitive dysfunction according to the present invention results in an improvement in the symptoms associated with the cognitive dysfunction.

[0318] Although cognitive dysfunction may be considered a condition that should be treated independently of any other conditions, disorders, or symptoms that an individual may have, several psychiatric and neurological disorders are associated with cognitive dysfunction. Of note, the relationship between cognitive dysfunction and psychiatric disorders is often bidirectional. Not only can psychiatric disorders negatively affect cognitive function, but cognitive dysfunction can also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0319] In many cases, resting-state networks implicated in cognitive dysfunction are also implicated in these disorders.

[0320] 5-MeO-DMT is able to interrupt established functional connectivity patterns of resting-state networks. This disruption results in a reset of pathological, poorly connected brain connections as the network rewires. New, healthy functional connections are established, and this has a lasting effect.

[0321] Disorders characterized by depressive episodes

[0322] Several disorders are characterized by depressive episodes.

[0323] A depressive episode is a period of depressed mood and / or loss of interest in most activities.

[0324] For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms within the same 2-week period that represent a change from previous functioning; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

[0325] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0326] Patients with disorders characterized by depressive episodes experience cognitive impairment. It involves impairments in executive function, learning and memory, processing speed, and concentration and attention.

[0327] Cognitive impairment is included as a diagnostic criterion for disorders characterized by depressive episodes. It can be assessed using the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS measures.

[0328] The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0329] The items are overt sadness; reported sadness; inner tension; decreased sleep; decreased appetite; difficulty concentrating; laziness; sensory loss; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6. The overall score ranges from 0 to 60.

[0330] Difficulty concentrating was described as difficulty focusing thoughts, resulting in an inability to concentrate, with a scale ranging from "No difficulty concentrating" (=0), "Occasional difficulty concentrating thoughts." (=1, 2, or 3), "Difficulty concentrating and sustaining thoughts, resulting in reduced ability to read or have a conversation." (=3, 4, or 5) to "Unable to read or have a conversation easily." (=6).

[0331] The Hamilton Depression Rating Scale (HAM-D) allows clinicians to assess the nature and severity of mood disturbances in a patient population. The scale consists of 21 items, but only the first 17 items (depressed mood; guilt; suicidality; initial insomnia; nighttime insomnia; delayed insomnia; work and interests; retardation; agitation; mental anxiety; physical anxiety; gastrointestinal somatic symptoms; general somatic symptoms; genital symptoms; hypochondriasis; weight loss; insight) are used for scoring.

[0332] For most questions, the score ranges from 0 to 4, with 4 representing more severe signs of depression. A few questions extend the range to only 2. A total score is calculated, which can then be compared to previous scores or can be contrasted to a predefined cutoff score.

[0333] In the context of the “retardation” item, the questionnaire assessed delays in thinking and speech, impaired concentration, and reduced motor activity.

[0334] The British Columbia Cognitive Complaints Inventory (BC-CCI) is a rapid screening self-rating tool that assesses perceived cognitive difficulties in patients with disorders characterized by depressive episodes.

[0335] The scale consists of 6 items that assess difficulties with concentration, memory, expressing thoughts, finding words, slow thinking, and problem solving over the past 7 days. The scores for each item (ranging from 0 (not at all) to 3 (a lot)) are added together to give a total score ranging from 0 to 18; higher scores indicate more severe cognitive complaints.

[0336] Cognitive dysfunction in patients suffering from a disorder characterized by depressive episodes may also be assessed, for example, using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score, or one or more component scores thereof.

[0337] In patients with disorders characterized by depressive episodes, altered functional connectivity within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes associated with rumination; impaired concentration and physiological arousal is observed.

[0338] Treatment of patients suffering from a disorder characterized by a depressive episode (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the disorder characterized by a depressive episode.

[0339] A reduction or elimination of cognitive dysfunction in a patient suffering from a disorder characterized by a depressive episode is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0340] The reduction or elimination of cognitive dysfunction in a patient suffering from a disorder characterized by a depressive episode occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0341] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from a disorder characterized by a depressive episode (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0343] Reduction or elimination of cognitive dysfunction, particularly retardation, in patients suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] A reduction or elimination of cognitive dysfunction (particularly retardation) in patients suffering from a disorder characterized by a depressive episode (reflected by an improvement in the score of the HAM-D item retardation) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item retardation) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] Reduction or elimination of cognitive dysfunction in a patient suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in a score on the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0346] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) in patients suffering from a disorder characterized by a depressive episode occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0347] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by a depressive episode is reflected in an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14 and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0348] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from a disorder characterized by a depressive episode (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) in patients suffering from a disorder characterized by a depressive episode preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0349] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in a patient suffering from a disorder characterized by a depressive episode is reflected in an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14 and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0350] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from a disorder characterized by a depressive episode (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) in patients suffering from a disorder characterized by a depressive episode preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0351] As described above, cognitive dysfunction is closely related to disorders characterized by depressive episodes. Therefore, improvements in cognitive dysfunction will also lead to improvements in disorders characterized by depressive episodes. Since cognitive dysfunction also affects other aspects of disorders characterized by depressive episodes, the inventors conclude that improvements in cognitive dysfunction, particularly reduction or elimination of difficulty concentrating, will further contribute to overall improvements in disorders characterized by depressive episodes.

[0352] Improvement in disorders characterized by depressive episodes (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction is observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0353] Improvement of the disorder characterized by depressive episodes in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of the disorder characterized by depressive episodes in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0354] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects how a person feels, thinks, and behaves, and can lead to a variety of emotional and physical problems.

[0355] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder (TRD).

[0356] Cognitive dysfunction is common in patients with major depressive disorder (MDD) and is prevalent across multiple cognitive domains, including memory, executive function, attention, and emotional processing.

[0357] Impairments in executive function, learning and memory, processing speed, and concentration and attention are associated with poor outcomes in psychosocial and occupational domains. In patients with MDD, cognitive dysfunction is the main mediator of functional impairment, especially through impacts on work performance. Impairments in attention, in particular, negatively impact daily functioning and lead to poorer clinical outcomes.

[0358] Cognitive dysfunction is included as a diagnostic criterion for MDD, particularly a reduced ability to think or concentrate. Relevant cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention. Impairment in attention negatively affects daily functioning and leads to poor clinical outcomes. Cognitive dysfunction is associated with poor outcomes in psychosocial and occupational domains.

[0359] Cognitive impairment in patients with MDD can be assessed using the British Columbia Cognitive Complaints Questionnaire (BC-CCI) or as part of the HAM-D or MADRS test. It can also be assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0360] In patients with MDD, functional connectivity disturbances and modulations within and / or between multiple resting-state networks, including the DMN, salience network, and executive control network, were observed. Functional connectivity was significantly different from that observed in healthy controls.

[0361] More specifically, altered functional connectivity within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes associated with rumination; impaired concentration and physiological arousal were observed.

[0362] Treatment of patients suffering from MDD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the MDD.

[0363] A reduction or elimination of cognitive dysfunction in a patient suffering from MDD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0364] The reduction or elimination of cognitive dysfunction in patients suffering from MDD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0365] A reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from MDD is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from MDD (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0367] Reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0368] The reduction or elimination of cognitive dysfunction in patients suffering from MDD (reflected by an improvement in the score of the HAM-D item slowness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item slowness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0369] Reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected in at least an improvement in a score on the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0370] The reduction or elimination of cognitive dysfunction in patients suffering from MDD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0371] Reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] The reduction or elimination of cognitive dysfunction in patients suffering from MDD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0373] Reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected in at least an improvement in a score on the MATRICS Consensus Cognitive Battery (MCCB) score, or one or more component scores thereof, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] The reduction or elimination of cognitive dysfunction in patients suffering from MDD (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0375] As mentioned above, cognitive dysfunction is closely related to MDD. Therefore, improvement of cognitive dysfunction will also lead to improvement of MDD. Since cognitive dysfunction also affects other aspects of MDD, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentrating, will further contribute to the overall improvement of MDD.

[0376] Improvements in MDD (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0377] Improvement in MDD in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in MDD in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0378] Postpartum depression (PPD) is a debilitating mood disorder that develops during pregnancy or within 4 weeks after childbirth. More than 50% of women may experience a brief period of low mood or tearfulness after childbirth, but a small percentage of women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be about 15%.

[0379] Patients suffering from PPD may suffer from a treatment-resistant form of the disorder.

[0380] PPD can also have an impact on cognition. Many people with PPD often complain of memory loss that affects their daily activities.

[0381] Depression during the postpartum period not only affects the mother's overall health, but it also affects the way the mother interacts with her child, which can affect the child's development.

[0382] Cognitive impairment in patients with PPD can be assessed using the British Columbia Cognitive Complaints Questionnaire (BC-CCI) or as part of the HAM-D or MADRS test. It can also be assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0383] In patients with PPD, significant changes in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition can be observed. PPD is associated with functional impairments in resting-state networks, such as within and / or between the default mode network and the frontoparietal network.

[0384] Treatment of patients suffering from PPD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of PPD.

[0385] A reduction or elimination of cognitive dysfunction in a patient suffering from PPD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0386] The reduction or elimination of cognitive dysfunction in patients suffering from PPD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] A reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in a patient suffering from PPD is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0388] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from PPD (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0389] Reduction or elimination of cognitive dysfunction in a patient suffering from PPD is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0390] The reduction or elimination of cognitive dysfunction in patients suffering from PPD (reflected by an improvement in the score of the HAM-D item slowness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item slowness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0391] Reduction or elimination of cognitive dysfunction in a patient suffering from PPD is reflected in at least an improvement in a score on the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0392] The reduction or elimination of cognitive dysfunction in patients suffering from PPD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0393] Reduction or elimination of cognitive dysfunction in a patient suffering from PPD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0394] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) in patients suffering from PPD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0395] Reduction or elimination of cognitive dysfunction in a patient suffering from PPD is reflected in at least an improvement in a score on the MATRICS Consensus Cognitive Battery (MCCB) score, or one or more component scores thereof, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0396] The reduction or elimination of cognitive dysfunction in patients suffering from PPD (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0397] As mentioned above, cognitive dysfunction is closely related to PPD. Therefore, improvement of cognitive dysfunction will also lead to improvement of PPD. Since cognitive dysfunction also affects other aspects of PPD, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentrating, will further contribute to the overall improvement of PPD.

[0398] Improvements in PPD (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0399] Improvement in PPD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PPD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0400] Furthermore, cognitive impairment can impair maternal functioning.

[0401] For example, the Barkin Index of Maternal Function (BIMF) can be used to assess maternal function. The index is designed to measure function within one year after childbirth. The BIMF is a 20-item self-report function measurement. Each item is scored from 0 to 6, making the maximum total score 120 points. The higher the score, the better the assessment of maternal function.

[0402] BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and regulation.

[0403] A BIMF of 95 or below is considered herein to represent mild impairment in maternal functioning, a score of 80 or below is considered herein to represent impaired maternal functioning, and a score of 65 or below is considered herein to represent severe impairment in maternal functioning.

[0404] The inventors have determined that increased scores on the MADRS item "Difficulty concentrating" have a negative impact on maternal functioning (maternal ability related to interaction with the infant and maternal self-care).

[0405] An increase in the score on the MADRS item "difficulty concentrating" impaired infant care and management. Conversely, an improvement on this MADRS item led to an improvement in maternal functioning, particularly in the BIMF functional domain infant care and / or management.

[0406] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve improvements in cognitive function, particularly reduction or elimination of difficulty concentrating.

[0407] The inventors also concluded that reducing or eliminating difficulty concentrating by treating PPD patients not only resulted in a decrease in the total MADRS score, but also resulted in an improvement in maternal functioning as reflected by an increase in the BIMF score.

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

[0409] Improvement in maternal function in patients suffering from PPD is reflected in at least an improvement in BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] Improvement in maternal function (as reflected by improvement in BIMF total score) in patients suffering from PPD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0411] Persistent depressive disorder

[0412] Persistent depressive disorder, also called dysthymia, is a chronic form of depression. It is diagnosed if depression is present most of the time, most of the days, for at least 2 years. Any symptom-free period is less than 2 months.

[0413] To be depressed, two or more of the following symptoms must be present: 1. Hopelessness 2. Lack of energy or fatigue 3. Low self-esteem 4. Decreased sleep (insomnia) or increased sleep (hypersomnia) 5. Loss of appetite or overeating 6. Difficulty making decisions or concentrating.

[0414] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0415] Cognitive dysfunction is common in patients with persistent depressive disorder and is prevalent across multiple different cognitive domains, including memory, executive function, attention, and emotional processing.

[0416] Impairments in executive function, learning and memory, processing speed, and concentration and attention are associated with poor outcomes in psychosocial and occupational domains. In patients with persistent depressive disorder, cognitive impairment is the main mediator of functional impairment, especially through impacts on work performance. Impairments in attention, in particular, have a negative impact on daily functioning and lead to poorer clinical outcomes.

[0417] Cognitive dysfunction is included as a diagnostic criterion for persistent depressive disorder, particularly a reduced ability to think or concentrate. Relevant cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention. Impairment in attention negatively affects daily functioning and leads to poor clinical outcomes. Cognitive dysfunction is associated with poor outcomes in psychosocial and occupational domains.

[0418] Cognitive impairment in patients with persistent depressive disorder can be assessed using the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS test. It can also be assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0419] In patients with persistent depressive disorder, altered functional connectivity within and / or between several brain regions was observed that are involved in processing, regulation, emotional memory, cognitive processes associated with rumination, impaired concentration, and physiological arousal. Functional connectivity disturbances and modulations were observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity was significantly different from that observed in healthy controls.

[0420] Treatment of patients suffering from persistent depressive disorder (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the persistent depressive disorder.

[0421] A reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0422] The reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0423] A reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score of the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0424] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from persistent depressive disorder (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0425] Reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0426] The reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder (reflected by an improvement in the score of the HAM-D item slowness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item slowness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0427] Reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0428] The reduction or elimination of cognitive dysfunction (reflected by the improvement of SCIP score) in patients suffering from persistent depressive disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by the improvement of SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0429] Reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0430] The reduction or elimination of cognitive dysfunction (reflected by an improvement in MoCA score) in patients suffering from persistent depressive disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0431] Reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is reflected in at least an improvement in the score of the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0432] The reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0433] As mentioned above, cognitive dysfunction is closely related to persistent depressive disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of persistent depressive disorder. Since cognitive dysfunction also affects other aspects of persistent depressive disorder, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentrating, will further contribute to the overall improvement of persistent depressive disorder.

[0434] Improvements in persistent depressive disorder (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0435] Improvement of persistent depressive disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of persistent depressive disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0436] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms typically starting in the fall and easing in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0437] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0438] Cognitive impairment associated with SAD can affect concentration, perception, attention, or memory. Importantly, cognitive abilities in patients with SAD are impaired not only in the winter but also in the summer. Compared with controls, patients with SAD show significant season-independent impairments in tasks measuring working memory, cognitive processing speed, and motor speed.

[0439] Cognitive impairment in patients with seasonal affective disorder can be assessed using the British Columbia Cognitive Complaints Questionnaire (BC-CCI) or as part of the HAM-D or MADRS test. It can also be assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0440] In patients with seasonal affective disorder, altered functional connectivity was detected within and / or between resting-state networks associated with visual, sensorimotor, and attention processing compared to healthy controls. For example, attention deficits are a common symptom in patients suffering from seasonal affective disorder. RS-fMRI revealed selective changes in functional connectivity in brain regions associated with attention processing.

[0441] Treatment of patients suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the seasonal affective disorder.

[0442] A reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0443] The reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from seasonal affective disorder is reflected in at least an improvement in the score of the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0445] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from seasonal affective disorder (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0446] Reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0447] The reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder (reflected by an improvement in the score of the HAM-D item slowness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item slowness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] Reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected in at least an improvement in a score on the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0449] The reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] Reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0451] The reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0452] Reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected in at least an improvement in a score on the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] The reduction or elimination of cognitive dysfunction in patients suffering from seasonal affective disorder (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] As mentioned above, cognitive dysfunction is closely related to seasonal affective disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of seasonal affective disorder. Since cognitive dysfunction also affects other aspects of seasonal affective disorder, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentrating, will further contribute to the overall improvement of seasonal affective disorder.

[0455] Improvements in seasonal affective disorder (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0456] Improvement in seasonal affective disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] Bipolar disorder (BD) is a mental health condition characterized by dramatic mood swings, including periods of low moods (major depressive episodes) and high moods (manic or hypomanic episodes). Bipolar disorder is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0458] If at least one manic episode occurs (with or without a depressive episode), BD is classified as bipolar disorder type I. If at least one hypomanic episode (but not a full manic episode) and one major depressive episode occur, BD is classified as bipolar disorder type II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

[0459] Patients suffering from BD (including bipolar disorder type I and bipolar disorder type II) may suffer from treatment-resistant forms of the disorder.

[0460] In BD, including bipolar I and bipolar II, cognitive impairment exists throughout acute affective states as well as between these states during periods of calm.

[0461] Cognitive impairment in BD is observed in multiple domains and is particularly evident in verbal and working memory, attention, and executive function.

[0462] Cognitive impairment in patients with BD can be assessed using the British Columbia Cognitive Complaints Questionnaire (BC-CCI) or as part of the HAM-D or MADRS test. It can also be assessed using the Screening for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0463] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. BDRS has been validated and can be used for clinical purposes by trained assessors. According to clinical interviews, the BDRS project assesses the severity of depression and / or mixed symptoms that the patient currently and in the past few days have shown. If the current symptoms are inconsistent with the symptoms of the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the highest possible score is 60. The higher the score, the higher the severity.

[0464] The problems addressed are: depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopelessness; suicidal ideation; guilt; psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation.

[0465] Each of these aspects was assessed and scored 0, 1, 2, or 3.

[0466] If there is no subjective report indicating the presence of decreased attention, concentration or memory and the functional impairment caused by them, the impaired concentration and memory will be scored as 0 points; if attention, concentration or memory is slightly impaired but there is no functional impairment, it will be scored as 1 point (mild); if attention, concentration or forgetfulness is severely impaired and there is some functional impairment, it will be scored as 2 points (moderate); if concentration or memory is significantly impaired and there is severe functional impairment, such as inability to read or watch TV, it will be scored as 3 points (severe).

[0467] Patients with bipolar disorder display characteristic abnormalities in the intrinsic organization and interconnectivity of resting-state networks.

[0468] Resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity of specific regions within and / or between the default mode network, the salience network, and the central executive network compared with healthy controls.

[0469] Treatment of patients suffering from BD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of BD.

[0470] A reduction or elimination of cognitive dysfunction in patients suffering from BD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0471] The reduction or elimination of cognitive dysfunction in patients suffering from BD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] A reduction or elimination of cognitive dysfunction, particularly impairment of concentration and memory, in patients suffering from BD is reflected at least in an improvement in the score of the BDRS items impairment of concentration and memory at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0473] Reduction or elimination of cognitive impairment (particularly impaired concentration and memory) in patients suffering from BD (reflected by improvements in scores for the BDRS items impaired concentration and memory) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] The reduction or elimination of cognitive dysfunction (particularly impairment of concentration and memory) (reflected by an improvement in the scores of the BDRS items impairment of concentration and memory) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] A reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from BD is reflected in at least an improvement in the score of the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0476] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) in patients suffering from BD (reflected by an improvement in the score of the MADRS item difficulty concentrating) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating) (reflected by an improvement in the score of the MADRS item difficulty concentrating) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0477] Reduction or elimination of cognitive dysfunction in a patient suffering from BD is reflected in at least an improvement in the score of the HAM-D item retardation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0478] The reduction or elimination of cognitive dysfunction in patients suffering from BD (reflected by an improvement in the score of the HAM-D item slowness) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the score of the HAM-D item slowness) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0479] Reduction or elimination of cognitive dysfunction in a patient suffering from BD is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0480] The reduction or elimination of cognitive dysfunction in patients suffering from BD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0481] Reduction or elimination of cognitive dysfunction in a patient suffering from BD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0482] The reduction or elimination of cognitive dysfunction in patients suffering from BD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0483] Reduction or elimination of cognitive dysfunction in a patient suffering from BD is reflected in at least an improvement in the score of the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] The reduction or elimination of cognitive dysfunction in patients suffering from BD (reflected by an improvement in the MCCB score or one or more component scores thereof) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MCCB score or one or more component scores thereof) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] As mentioned above, cognitive dysfunction is closely related to BD. Therefore, improvement of cognitive dysfunction will also lead to improvement of BD. Since cognitive dysfunction also affects other aspects of BD, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentrating, will further contribute to the overall improvement of BD.

[0486] Improvements in BD (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0487] Improvement of BD in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of BD in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] Anxiety disorders

[0489] Anxiety disorders are mental health conditions. Symptoms include feelings of nervousness, panic, and fear, as well as sweating and a racing heartbeat. Anxiety involves a complex system of cognitive, emotional, physiological, and behavioral responses related to preparation for an anticipated event or situation that is perceived as a threat.

[0490] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0491] Several domains of cognitive function are dysregulated in anxiety states and in disorders more generally, including spatial working memory, executive function, and attentional biases.

[0492] Hamilton Anxiety Rating Scale (HAM-A) is used to measure the severity of anxiety symptoms in various anxiety disorders (panic disorder, phobia and generalized anxiety disorder). The scale consists of 14 items, each of which is defined by a series of symptoms, and measures mental anxiety (mental agitation and psychological distress) and somatic anxiety (physical discomfort associated with anxiety). The 5th item is "intelligence", which is defined as "difficulty concentrating and poor memory". The scoring range of each item is 0 (absent) to 4 (severe), and the total score range is 0-56, wherein <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe.

[0493] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0494] Anxiety disorders are studied by functional magnetic resonance imaging. Generally speaking, all anxiety disorders show abnormalities in the default mode network (DMN). Other networks affected by these disorders are the salience network (SN) and the somatomotor network (SMN). Relative to the DMN, the resting state balance within and / or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

[0495] Treatment of patients suffering from anxiety disorders (including treatment-resistant forms of the disorders) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the anxiety disorder.

[0496] A reduction or elimination of cognitive dysfunction in patients suffering from anxiety disorders is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0497] The reduction or elimination of cognitive dysfunction in patients suffering from anxiety disorders occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from anxiety disorders is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0499] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from anxiety disorders (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0500] Reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder is reflected in at least an improvement in the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0501] The reduction or elimination of cognitive dysfunction in patients suffering from anxiety disorders (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] Reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder is reflected in at least an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0503] The reduction or elimination of cognitive dysfunction in patients suffering from anxiety disorders (reflected by an improvement in MoCA scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in MoCA scores) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0504] As mentioned above, cognitive dysfunction is closely related to anxiety disorders. Therefore, improvement of cognitive dysfunction will also lead to improvement of anxiety disorders. Since cognitive dysfunction can also affect other aspects of anxiety disorders, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of anxiety disorders.

[0505] Improvements in anxiety disorders (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0506] Improvement of anxiety disorders in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of anxiety disorders in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] Separation anxiety disorder is characterized by excessive anxiety about leaving home and / or being separated from people to whom the patient has a strong emotional attachment.

[0508] Separation situations can cause patients great distress, and they may have difficulty attending school or work because of the separation. People with separation anxiety disorder may also feel excessively anxious about unwelcome events that happen to important people in their lives, such as family members.

[0509] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0510] Several domains of cognitive function are dysregulated in anxiety states and in disorders more generally, including spatial working memory, executive function, and attentional biases.

[0511] Cognitive dysfunction is assessed as part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0512] Functional magnetic resonance imaging of individuals with separation anxiety disorder reveals alterations in functional connectivity within and / or between resting-state networks involved in anxiety.

[0513] Treatment of patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the separation anxiety disorder.

[0514] A reduction or elimination of cognitive dysfunction in patients suffering from separation anxiety disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0515] The reduction or elimination of cognitive dysfunction in patients suffering from separation anxiety disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0516] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from separation anxiety disorder is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0517] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from separation anxiety disorder (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] Reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder is reflected in at least an improvement in the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0519] The reduction or elimination of cognitive dysfunction in patients suffering from separation anxiety disorder (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0520] Reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder is reflected in at least an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0521] The reduction or elimination of cognitive dysfunction in patients suffering from separation anxiety disorder (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0522] As mentioned above, cognitive dysfunction is closely related to separation anxiety disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of separation anxiety disorder. Since cognitive dysfunction can also affect other aspects of separation anxiety disorder, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of separation anxiety disorder.

[0523] Improvements in separation anxiety disorder (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0524] Improvement in separation anxiety disorder in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in separation anxiety disorder in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] Agoraphobia is the fear of situations or places that may cause feelings of panic, entrapment, helplessness, or embarrassment.

[0526] People with agoraphobia may have difficulty leaving the house. The thought of leaving the house may cause considerable anxiety, even leading to avoidance. Fear of crowds, travel, elevators, movie theaters, shopping malls, etc. may cause significant challenges.

[0527] People with agoraphobia may also experience recurring panic attacks.

[0528] Patients suffering from agoraphobia may suffer from a treatment-resistant form of the disorder.

[0529] Several domains of cognitive function are dysregulated in anxiety states and in disorders more generally, including spatial working memory, executive function, and attentional biases.

[0530] Cognitive dysfunction is assessed as part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0531] Functional magnetic resonance imaging of individuals with agoraphobia reveals alterations in functional connectivity within and / or between resting-state networks involved in anxiety.

[0532] Treatment of patients suffering from agoraphobia (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the agoraphobia.

[0533] A reduction or elimination of cognitive dysfunction in patients suffering from agoraphobia is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0534] The reduction or elimination of cognitive dysfunction in patients suffering from agoraphobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from agoraphobia is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0536] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from agoraphobia (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] Reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia is reflected in at least an improvement in the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0538] The reduction or elimination of cognitive dysfunction (reflected by the improvement of SCIP score) in patients suffering from agoraphobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by the improvement of SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] Reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia is reflected in at least an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0540] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) in patients suffering from agoraphobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0541] As mentioned above, cognitive dysfunction is closely related to agoraphobia. Therefore, improvement of cognitive dysfunction will also lead to improvement of agoraphobia. Since cognitive dysfunction will also affect other aspects of agoraphobia, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of agoraphobia.

[0542] Improvements in agoraphobia (as reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0543] Improvement in agoraphobia in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in agoraphobia in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and uncontrollable worry about a variety of situations and problems. People with GAD may anticipate disasters and may worry excessively about money, health, family, work, or other issues.

[0545] Generalized anxiety disorder is diagnosed when an individual experiences persistent worry about everyday challenges that is out of proportion to the perceived threat. People with GAD typically experience excessive fear that lasts for months to years.

[0546] GAD can interfere with social, occupational, or other important areas of functioning.

[0547] Patients suffering from GAD may suffer from a treatment-resistant form of the disorder.

[0548] People with GAD report at least three of the following six symptoms: restlessness, fatigue, impaired concentration, irritability, muscle tension, and sleep disturbance.

[0549] Elderly patients with GAD have poorer cognitive function, particularly short-term memory, compared with age-matched non-anxious individuals.

[0550] Impairments in global cognition as well as inductive reasoning and inhibition were found to be risk factors for developing GAD later in life.

[0551] Difficulty concentrating is thought to be one mechanism by which worry increases clinical severity. Difficulty concentrating can cause significant distress and impaired role functioning.

[0552] Assessment of cognitive dysfunction is part of the Generalized Anxiety Disorder Questionnaire and the Hamilton Anxiety Rating Scale (HAM-A) of DSM 5. The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0553] GAD patients also show altered functional connectivity, particularly within the default mode network.

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

[0555] A reduction or elimination of cognitive dysfunction in patients suffering from GAD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] The reduction or elimination of cognitive dysfunction in patients suffering from GAD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0558] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from GAD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0563] As mentioned above, cognitive dysfunction is closely related to GAD. Therefore, improvement of cognitive dysfunction will also lead to improvement of GAD. Since cognitive dysfunction also affects other aspects of GAD, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of GAD.

[0564] Improvements in GAD (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0565] Improvement in GAD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in GAD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety.

[0567] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations and may cause impairment in school, work, or interpersonal relationships.

[0568] Patients suffering from SAD may suffer from a treatment-resistant form of the disorder.

[0569] Cognitive dysfunction has also been linked to SAD.

[0570] Several domains of cognitive function are dysregulated in anxiety states and in disorders more generally, including spatial working memory, executive function, and attentional biases.

[0571] Cognitive dysfunction is assessed as part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0572] Anxiety disorders show abnormalities within and / or between the default mode network (DMN), salience network (SN), and somatomotor network (SMN). In patients with social anxiety disorder, altered functional connectivity is mainly present in the DMN and SN.

[0573] Treatment of patients suffering from SAD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of SAD.

[0574] A reduction or elimination of cognitive dysfunction in a patient suffering from SAD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0575] The reduction or elimination of cognitive dysfunction in patients suffering from SAD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0576] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0577] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0578] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0579] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0580] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0581] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from SAD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0582] As mentioned above, cognitive dysfunction is closely related to SAD. Therefore, improvement of cognitive dysfunction will also lead to improvement of SAD. Since cognitive dysfunction also affects other aspects of SAD, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of SAD.

[0583] Improvements in SAD (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0584] Improvement in SAD (reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD (reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0585] People with panic disorder experience spontaneous panic attacks, sudden onset of intense fear or discomfort that peaks within a few minutes.

[0586] Panic attacks are characterized by multiple somatic symptoms of anxiety, including sweating, shaking, trembling, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0587] In addition, the disorder can often be characterized by anxiety about future panic attacks. The patient may become extremely concerned about the possibility of another attack.

[0588] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0589] Several domains of cognitive function are dysregulated in anxiety states and in more general disorders, including spatial working memory, executive function, and attentional biases. Patients with panic disorder have been found to have abnormalities in the early processing of stimuli, manifested by an increased startle response and decreased habituation compared with individuals without panic disorder.

[0590] Decreased memory function is a characteristic observed in patients with panic disorder.

[0591] Cognitive dysfunction can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A), one of the first scales developed to measure the severity of anxiety symptoms.

[0592] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0593] Patients with panic disorder show alterations in functional connectivity within and / or between the default mode network and the somatomotor network.

[0594] Functional magnetic resonance imaging of anxiety disorders reveals abnormalities in the default mode network (DMN), salience network (SN), and somatomotor / sensorimotor network (SMN). Relative to the DMN, the resting state balance within and / or between each of these networks (e.g., SMN and SN) may be abnormal in different anxiety disorders.

[0595] Treatment of patients suffering from panic disorder (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the panic disorder.

[0596] A reduction or elimination of cognitive dysfunction in patients suffering from panic disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0597] The reduction or elimination of cognitive dysfunction in patients suffering from panic disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0598] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0599] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from panic disorder (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] As mentioned above, cognitive dysfunction is closely related to panic disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of PD. Since cognitive dysfunction also affects other aspects of panic disorder, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty concentrating and poor memory, will further contribute to the overall improvement of panic disorder.

[0605] Improvements in panic disorder (reflected by a decrease in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0606] Improvement of panic disorder in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of panic disorder in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0607] A phobia is an anxiety disorder defined as a persistent and excessive fear of an object or situation.

[0608] People with phobias experience extreme anxiety when anticipating or coming into contact with the phobic stimulus. There are phobias of animals (spiders, snakes, dogs), natural environments (tornadoes, heights, water, fire), blood injections (needles, medical procedures), situations (flying, enclosed spaces), and others (those that don't fit into the previous categories).

[0609] Phobias usually cause a rapid onset of fear and are usually present for more than six months. The person will go to great lengths to avoid the feared stimulus. The fear and avoidance may cause significant distress and / or impairment in occupational, academic, or social functioning.

[0610] Patients suffering from phobias may suffer from a treatment-resistant form of the disorder.

[0611] Cognitive dysfunction in phobias can be directly assessed using the Hamilton Anxiety Rating Scale (HAM-A).

[0612] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0613] With successful treatment (such as, for example, cognitive behavioral therapy), abnormal conditions often return to normal.

[0614] In individuals with specific phobias, the amygdala, anterior cingulate cortex (ACC), and insular cortex all appear to be over-responsive to phobia-related stimuli in specific phobias. For example, functional neuroimaging studies have found that the dorsal part of the anterior cingulate cortex (dACC), which is part of the salience network, is over-responsive to phobia-related stimuli or the anticipation of such stimuli.

[0615] Treatment of patients suffering from phobias (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the phobia.

[0616] A reduction or elimination of cognitive dysfunction in a patient suffering from a phobia is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0617] The reduction or elimination of cognitive dysfunction in patients suffering from phobia occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] A reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobias is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobia (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0620] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobia is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0621] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobia (reflected by an improvement in MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobia is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0623] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from phobia (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0624] As mentioned above, cognitive dysfunction is closely related to phobia. Therefore, improvement of cognitive dysfunction will also lead to improvement of phobia. Since cognitive dysfunction also affects other aspects of phobia, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty in concentration and poor memory, will further contribute to the overall improvement of phobia.

[0625] Improvements in phobias (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0626] Improvement of phobia in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of phobia in patients who also suffer from associated cognitive dysfunction (as reflected by a decrease in CGI-S scores) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0627] Substance-induced anxiety disorder is an anxiety disorder in which anxiety or panic attacks occur after alcohol use, drug abuse, or medication use, or exposure to toxins. Substance-induced anxiety disorders cause significant panic or anxiety symptoms and may occur during periods of intoxication or withdrawal from substance or medication use.

[0628] The disorder causes significant distress and / or impairment in social, occupational, or other important areas of functioning.

[0629] During or shortly after taking a substance or medication, an individual with a substance / medication-induced anxiety disorder may feel nervous and worried, experience symptoms of negative thinking, may have difficulty concentrating or remembering things, may fear losing control or becoming insane or dying, may lose weight due to gastrointestinal problems, may experience chills, hot flashes, sweating, shivering, numbness or a racing heartbeat, trouble breathing, difficulty swallowing, or chest pain.

[0630] Patients suffering from substance / medication induced anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0631] Several domains of cognitive function are dysregulated in anxiety states and in disorders more generally, including spatial working memory, executive function, and attentional biases.

[0632] Cognitive dysfunction can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A), one of the first scales developed to measure the severity of anxiety symptoms.

[0633] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0634] Functional magnetic resonance imaging of individuals with substance / medication-induced anxiety disorders reveals alterations in functional connectivity within and / or between resting-state networks involved in anxiety.

[0635] Treatment of patients suffering from substance / drug induced anxiety disorders (including treatment-resistant forms of the disorders) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the substance / drug induced anxiety disorder.

[0636] A reduction or elimination of cognitive dysfunction in a patient suffering from a substance / medication induced anxiety disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0637] The reduction or elimination of cognitive dysfunction in patients suffering from substance / medication induced anxiety disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0638] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from substance / medication induced anxiety disorders is reflected in at least an improvement in the score of the HAM-A item "Intelligence" at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0639] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from substance / medication-induced anxiety disorders (reflected by an improvement in the score of the HAM-A item "Intelligence") occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the score of the HAM-A item "Intelligence") preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0640] Reduction or elimination of cognitive dysfunction in a patient suffering from substance / medication induced anxiety disorder is reflected in at least an improvement in the Screening for Cognitive Impairment in Psychiatry (SCIP) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0641] The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) in patients suffering from substance / medication-induced anxiety disorders occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] Reduction or elimination of cognitive dysfunction in a patient suffering from substance / medication induced anxiety disorder is reflected in at least an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] The reduction or elimination of cognitive dysfunction (reflected by an improvement in MoCA score) in patients suffering from substance / medication-induced anxiety disorders occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0644] As mentioned above, cognitive dysfunction is closely related to substance / drug-induced anxiety disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of substance / drug-induced anxiety disorder. Since cognitive dysfunction also affects other aspects of substance / drug-induced anxiety disorder, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of difficulty concentrating and poor memory, will further contribute to the overall improvement of substance / drug-induced anxiety disorder.

[0645] Improvements in substance / medication-induced anxiety disorders (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0646] Improvement of substance / drug-induced anxiety disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement of substance / drug-induced anxiety disorder in patients who also suffer from associated cognitive dysfunction (reflected by a decrease in CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] Somatic symptom disorder

[0648] Somatic symptom disorder is a mental disorder that is diagnosed when a person becomes so preoccupied with physical symptoms, such as pain, weakness, or shortness of breath, that it causes significant distress and / or problems functioning and / or disrupts daily life. Feelings and behaviors associated with the disorder are excessive or disproportionate.

[0649] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorder, the impairment is significant, and when it persists, the disorder may lead to disability.

[0650] In somatic symptom disorder (SSD), cognitive dysfunction is associated with perceptual distortions that over-amplify bodily sensations. Attention is focused on physical symptoms, and normal body sensations are attributed to physical illness (with possible catastrophic interpretations), leading to concerns about illness and fear that any physical activity may damage the body. Associated behavioral features may include repeated checking of the body for abnormalities, repeated requests for medical help and reassurance, and avoidance of physical activity.

[0651] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptoms - Adults measure. This measure includes 15 somatic symptoms. Respondents are asked to rate the severity of individual somatic symptoms during the past 7 days. Scores range from "0" ("not bothered at all"), "1" ("a little bothered") to "2" ("very bothered"). The total score can range from 0 to 30, with higher scores indicating greater severity of somatic symptoms. Cut-off values ​​of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0652] Alternatively, the Somatic Symptom Disorder-B Standard Scale (SSD-12) can be used. The cognitive, affective, and behavioral criteria are measured by 12 items, all scored between 0 and 4 (0=never, 1=rarely, 2=sometimes, 3=often, 4=very often). The scores are added together to produce a simple total score between 0 and 48. Attention diversion is considered to be "I can't concentrate on other things because of my physical discomfort" or "My physical discomfort takes up most of my day."

[0653] In addition, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) can be used to assess cognitive impairment in individuals with SSD.

[0654] Brain functional connectivity analysis revealed alterations within and / or between resting-state networks in patients with somatic symptom disorder compared with healthy controls. Alterations were found within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor networks. Somatic symptom disorder may be associated with alterations in sensory discrimination processing of somatic symptoms, which is affected by affective processing.

[0655] Treatment of patients suffering from somatic symptom disorder and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the somatic symptom disorder.

[0656] A reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0657] The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0658] Reduction or elimination of cognitive dysfunction in a patient suffering from somatic symptom disorder is reflected in at least an improvement in the Montreal Cognitive Assessment (MoCA) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] Reduction or elimination of cognitive dysfunction (reflected by improvement in MoCA score) in patients suffering from somatic symptom disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of cognitive dysfunction (reflected by improvement in MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] Reduction or elimination of cognitive dysfunction in a patient suffering from somatic symptom disorder is reflected in at least an improvement in the Mini-Mental State Examination (MMSE) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0661] The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder (reflected by an improvement in MMSE score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in MMSE score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0662] As mentioned above, cognitive dysfunction is closely related to somatic symptom disorder. Therefore, improvement of cognitive dysfunction will also lead to improvement of somatic symptom disorder. Since cognitive dysfunction also affects other aspects of somatic symptom disorder, the inventors conclude that improvement of cognitive function will further contribute to the overall improvement of somatic symptom disorder.

[0663] Improvements in somatic symptom disorder (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0664] Improvement in somatic symptom disorder (reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in somatic symptom disorder (reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] Obsessive-compulsive disorder and related disorders

[0666] Obsessive compulsive disorder (OCD) is a mental illness that causes repetitive unwanted thoughts or feelings (obsessions) or the urge to do something over and over again (compulsions). People may have both obsessions and compulsions.

[0667] Patients suffering from OCD may suffer from a treatment-resistant form of the disorder.

[0668] Patients with OCD show widespread dysfunction in multiple cognitive domains, such as memory, attention, executive function, and language. Their cognitive flexibility during task performance may be reduced because their cognitive resources are occupied by obsessive thoughts.

[0669] Cognitive dysfunction can be assessed using the 13-item Cognitive Assessment of Obsessions and Compulsions (CAIOC-13), which was developed specifically to explore cognitive difficulties in OCD. It provides a measure of neurocognitive-related functional abnormalities and can be used to measure the impact of OCD on daily functioning.

[0670] The CAIOC-13 explores 13 domains of cognitive functioning that are associated with psychosocial impairment in OCD: (1) dyslexia, (2) doubt, (3) laziness, (4) slowness, (5) indecisiveness, (6) perfectionism, (7) circadian rhythm, (8) anxiety, (9) procrastination, (10) flexibility, (11) executive function, (12) worry about the future, and (13) compulsive behavior.

[0671] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0672] Compared with age-matched healthy individuals, patients with OCD present with various forms of cognitive impairment, which are due to underlying neurobiological differences. Neuroimaging studies of patients with OCD using functional magnetic resonance imaging have shown altered functional connectivity within and / or between the frontoparietal, salience, and default mode networks.

[0673] Treatment of patients suffering from OCD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of OCD.

[0674] A reduction or elimination of cognitive dysfunction in a patient suffering from OCD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] The reduction or elimination of cognitive dysfunction in patients suffering from OCD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0676] Reduction or elimination of cognitive dysfunction in a patient suffering from OCD is reflected in at least an improvement in the score of the CAIOC-13 score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0677] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from OCD (reflected by an improvement in the CAIOC-13 score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the CAIOC-13 score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0678] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from OCD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0679] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from OCD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0680] Reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from OCD is reflected in at least an improvement in the score of the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0681] The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) in patients suffering from OCD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (particularly difficulty concentrating and poor memory) (reflected by an improvement in the SCIP score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0682] As mentioned above, cognitive dysfunction is closely related to OCD. Therefore, improvement of cognitive dysfunction will also lead to improvement of OCD. Since cognitive dysfunction also affects other aspects of OCD, the inventors conclude that improvement of cognitive dysfunction will further contribute to the overall improvement of OCD.

[0683] Improvements in OCD (reflected by reductions in CGI-S scores) in patients who also suffer from associated cognitive dysfunction are observed at about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0684] Improvement in OCD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in OCD (as reflected by a decrease in CGI-S score) in patients who also suffer from associated cognitive dysfunction preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] People with body dysmorphic disorder (BDD) falsely perceive imperfections in their appearance that disrupt their ability to live daily lives and are accompanied by disturbing thoughts, ritualistic behaviors, and emotional distress.

[0686] Patients suffering from BDD may suffer from a treatment-resistant form of the disorder.

[0687] BDD patients were found to have multiple cognitive impairments, including impairments in memory, decision-making, and attention shifting, as well as cognitive interference and inhibition of visuospatial search.

[0688] Cognitive rehabilitation may be useful in addressing cognitive deficits in patients with BDD.

[0689] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically evaluate cognitive dysfunction.

[0690] Functional magnetic resonance imaging of patients with BDD disorder revealed alterations within and / or between certain brain regions located within the default mode network, dorsal attention network, and salience network. These alterations in functional connectivity suggest that maladaptive self-referential thinking may reflect an inability to regulate the balance between internal and external attention.

[0691] Treatment of patients suffering from BDD (including treatment-resistant forms of the disorder) and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the BDD.

[0692] A reduction or elimination of cognitive dysfunction in a patient suffering from BDD is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0693] The reduction or elimination of cognitive dysfunction in patients suffering from BDD occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] Reduction or elimination of cognitive dysfunction in a patient suffering from BDD is reflected in at least an improvement in the score of the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] The reduction or elimination of cognitive dysfunction in patients suffering from BDD (reflected by an improvement in the MoCA score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an improvement in the MoCA score) preferably lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] Reduction or elimination of cognitive dysfunction in a patient suffering from BDD is reflected in at least an improvement in the score on the Screening for Cognitive Impairment in Psychiatry (SCIP) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0697] The reduction or elimination of cognitive dysfunction in patients suffering from BDD (reflected by an improvement in the SCIP score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction (reflected by an i...

Claims

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

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the cognitive dysfunction is a deficit or impairment in one or more cognitive domains selected from the group consisting of complex attention, executive function, learning and memory, language, sensorimotor function and social cognition.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1 or claim 2, wherein the cognitive dysfunction affects the cognitive domain complex attention.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the cognitive dysfunction affects one or more subdomains of the cognitive domain complex attention, the one or more subdomains being selected from sustained attention, divided attention, selective attention and processing speed.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the cognitive dysfunction affects the subdomain sustained attention of the cognitive domain complex attention.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the cognitive dysfunction is in the form of a neurocognitive disorder.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein the cognitive dysfunction is in the form of mild neurocognitive disorder.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein the cognitive dysfunction is in the form of severe neurocognitive disorder.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from persistent depressive disorder associated with the cognitive dysfunction.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the patient suffering from persistent depressive disorder suffers from a treatment-resistant form of the disorder.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from seasonal affective disorder associated with the cognitive dysfunction.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 25, wherein the patient suffering from seasonal affective disorder suffers from a treatment-resistant form of the disorder.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from bipolar disorder associated with the cognitive dysfunction.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 27, wherein the patient suffers from bipolar II disorder associated with the cognitive dysfunction.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 27, wherein the patient suffers from bipolar disorder type I associated with the cognitive dysfunction.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 27 to 29, wherein the patient suffers from a current major depressive episode.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 27 to 30, wherein the patient suffering from bipolar disorder suffers from a treatment resistant form of the disorder.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from an anxiety disorder associated with the cognitive dysfunction.

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

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from separation anxiety disorder associated with the cognitive dysfunction.

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

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from agoraphobia associated with the cognitive dysfunction.

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

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

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

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

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

42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from panic disorder associated with the cognitive dysfunction.

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

44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from a phobia associated with the cognitive dysfunction.

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

46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from substance / medication induced anxiety disorder associated with the cognitive dysfunction.

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

48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from somatic symptom disorder associated with the cognitive dysfunction.

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

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

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

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

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

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

55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from post-traumatic stress disorder (PTSD) associated with the cognitive dysfunction.

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

57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from a pain disorder associated with the cognitive dysfunction.

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

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

60. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from fibromyalgia associated with the cognitive dysfunction.

61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from migraine associated with the cognitive dysfunction.

62. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from psychiatric and behavioral disorders due to the use of psychoactive substances associated with the cognitive dysfunction.

63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 62, wherein the mental and behavioral disorders caused by the use of psychoactive substances suffered by the patient are substance use disorders (SUD) associated with the cognitive dysfunction.

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

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from a psychotic disorder associated with the cognitive dysfunction.

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

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from schizophrenia associated with the cognitive dysfunction.

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

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from Huntington's disease associated with the cognitive dysfunction.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from Parkinson's disease associated with the cognitive dysfunction.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from dementia associated with the cognitive dysfunction.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from Alzheimer's disease dementia associated with the cognitive dysfunction.

73. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from Parkinson's disease dementia associated with the cognitive dysfunction.

74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from Lewy body dementia associated with the cognitive dysfunction.

75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from vascular dementia associated with the cognitive dysfunction.

76. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from frontotemporal dementia associated with the cognitive dysfunction.

77. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from an eating disorder associated with the cognitive dysfunction.

78. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 77, wherein the patient suffering from an eating disorder suffers from a treatment-resistant form of the disorder.

79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 5, wherein the patient suffers from attention deficit hyperactivity disorder (ADHD) associated with the cognitive dysfunction.

80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 79, wherein the patient suffering from ADHD suffers from a treatment-resistant form of the disorder.

81. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from a personality disorder associated with the cognitive dysfunction.

82. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 81, wherein the patient suffers from schizotypal personality disorder associated with the cognitive dysfunction.

83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 81 or 82, wherein the patient suffers from a treatment-resistant form of the disorder.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from borderline personality disorder (BPD) associated with the cognitive dysfunction.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 84, wherein the patient suffering from BPD suffers from a treatment-resistant form of the disorder.

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from chronic fatigue syndrome associated with the cognitive dysfunction.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 5, wherein the cognitive dysfunction is caused by traumatic brain injury.

88. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the cognitive dysfunction is caused by HIV infection.

89. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 5, wherein the cognitive dysfunction is caused by COVID sequelae.

90. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 89, wherein said treatment reduces or eliminates said cognitive dysfunction.

91. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 90, wherein the reduction or elimination of the cognitive dysfunction is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 7 days; at 14 days; and / or at 28 days.

92. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 90, wherein the reduction or elimination of cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the reduction or elimination of cognitive dysfunction lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

93. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 9 to 92, wherein said treatment results in improvement of said diagnosed disorder in a patient who also suffers from an associated cognitive dysfunction.

94. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 93, wherein the improvement in the diagnosed disorder in a patient who also suffers from an associated cognitive dysfunction is observed as a decrease in the Clinical Global Impression - Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

95. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 93, wherein said improvement in said diagnosed disorder in a patient also suffering from an associated cognitive dysfunction occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, and wherein said improvement in said diagnosed disorder in a patient also suffering from an associated cognitive dysfunction persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

96. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient suffers from sleep disturbance associated with the cognitive dysfunction.

97. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 96, wherein the sleep disorder is insomnia.

98. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 96 or 97, wherein the patient suffers from idiopathic sleep disorder associated with the cognitive dysfunction.

99. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 96 to 98, wherein the patient suffers from a treatment-resistant form of the disorder.

100. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 96, 97 or 99, wherein the sleep disturbance occurs in a patient suffering from associated cognitive dysfunction and also suffering from a psychiatric or neurological disorder, such as a disorder characterized by depressive episodes, for example, major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorder; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementias, such as Alzheimer's disease dementia (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, and frontotemporal dementia; Huntington's disease (HD); eating disorders; Attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; or medical health conditions that result in associated psychiatric or neurological impairment, such as cognitive impairment caused by HIV infection, traumatic brain injury, or COVID sequelae.

101. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 100, wherein the treatment results in improvement of cognitive dysfunction and sleep disturbance, and further results in improvement of the related psychiatric or neurological disorder, or results in improvement of the medical health condition of the related psychiatric or neurological disorder.

102. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 90 to 101, wherein said treatment results in an improvement in said sleep disorder.

103. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 102, wherein the improvement in sleep disturbance is observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

104. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 102, wherein said improvement in said sleep disturbance occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score, and wherein said improvement in said sleep disturbance persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

105. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 102, wherein said improvement in said sleep disturbance is observed on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, and preferably lasts until at least 14 days, more preferably until at least 28 days.

106. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 105, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

107. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 106, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

108. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 106, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

109. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 106, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

110. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 107, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

111. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 107 or 110, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

112. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 111, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

113. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 1 to 107 or 110, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

114. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 113, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

115. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 110 to 114, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

116. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claims 106 to 115, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

117. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 116, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

118. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 117, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

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