5-Methoxy-N,N-dimethyltryptamine for the treatment of cognitive dysfunction

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat patients suffering from cognitive dysfunction, where the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via an intravenous, intramuscular or subcutaneous route.

Description

[Technical Field]

[0001] The present invention relates to an improved method for treating cognitive dysfunction.Cognitive dysfunction can occur in patients who suffer from mental disorders or nervous system disorders, or medical conditions that lead to related mental or nervous system conditions.Cognitive dysfunction can also occur in patients who suffer from sleep disorders, such as insomnia.

[0002] Cognitive dysfunction also occurs in unspecified neurocognitive disorders, i.e., disorders that exhibit symptoms characteristic of neurocognitive disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any etiologically related disorder.

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

[0004] Cognitive dysfunction refers to deficits in attention, verbal and non-verbal 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 and neurological disorders. Cognitive dysfunction also occurs in patients suffering from certain medical conditions that lead to related psychiatric or neurological conditions.

[0006] Cognitive dysfunction can take the form of a neurocognitive disorder, where cognitive dysfunction is a defining feature of the disorder.

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

[0008] Cognitive problems are associated with a lower quality of life, greater depression, greater anxiety, greater stress, and poorer overall mental health.

[0009] Cognitive dysfunction requires detailed evaluation and management.

[0010] Cognitive dysfunction is treated by non-pharmacological approaches through cognitive, physical, and social activities, as well as by pharmacological approaches. Some interventions focus primarily on improving quality of life and limiting residual deficits.

[0011] Physical activity, cognitive training and exercise, adequate sleep, and relaxation techniques can aid cognitive health. Environmental approaches, such as reducing noise around the patient, can help patients focus on tasks and reduce distractions, 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 report impaired concentration, which negatively impacts their daily functioning, and these attention problems do not improve with current first-line treatments. Selective serotonin reuptake inhibitors (SSRIs), currently the first-line class of drug treatment for depression, have generally not been shown to reduce or eliminate cognitive dysfunction. Many studies, primarily observational or using multiple drug combinations, have failed to demonstrate changes in sustained, selective, or divided attention despite improvements in mood symptoms.

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

[0015] Thus, there is a need for improved methods for the treatment of cognitive dysfunction. Summary of the Invention

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

[0017] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens that have a superior safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are associated with higher patient compliance (including higher treatment initiation rates) than previously described therapies. A still further object of the present invention is to identify specific disease states and specific disease subgroups that would 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 a patient suffering from cognitive dysfunction.

[0019] The present invention also relates to 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from cognitive dysfunction, wherein the cognitive dysfunction is a deficit or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor 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 a patient suffering from a cognitive dysfunction, wherein the cognitive dysfunction affects one or more subdomains of the cognitive domain complex attention selected from sustained attention, divided attention, selective attention, and processing speed, in particular the subdomain of the cognitive domain complex attention sustained attention.

[0021] According to the present invention, cognitive dysfunction takes the form of a neurocognitive disorder, for example a mild neurocognitive disorder or a severe neurocognitive disorder.

[0022] Cognitive dysfunction may be associated with psychiatric or neurological disorders, for example, disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorders (BD) such as bipolar I disorder and bipolar II disorder; anxiety disorders, e.g., separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, e.g., chronic pain, fibromyalgia, and migraine; and psychotropic substance use-related disorders. These conditions may occur in patients suffering from mental and behavioral disorders resulting from cognitive impairment, such as substance use disorders (SUDs); psychiatric disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease (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 conditions leading to related psychiatric or neurological conditions, such as HIV infection, traumatic brain injury, or medical conditions leading to cognitive dysfunction due to COVID sequelae.

[0023] Patients may also suffer from sleep disorders that are associated with cognitive dysfunction.

[0024] The present invention also provides dosage ranges and regimens useful for treating 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] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a hallucinogenic high. A dose of about 1 mg to about 10 mg of 5-MeO-DMT, or an equimolar amount of a pharmaceutically acceptable salt, may be administered. DETAILED DESCRIPTION OF THE INVENTION

[0027] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming that an equimolar amount is used.

[0028] As used in the context of the present invention, a "patient" to be treated is a human subject who, according to accepted medical practice, is suffering from cognitive dysfunction or who, according to accepted medical practice, is diagnosed by a licensed professional with a psychiatric or nervous system disorder associated with cognitive dysfunction, in which case assessment of cognitive dysfunction may or may not be part of the diagnosis.

[0029] Diagnosis of mental or nervous system disorders may be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will be apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or patient groups that will particularly benefit from treatment according to the present invention. Diagnosis is made by a physician or psychologist. It is not sufficient for the human subject to consider themselves to be suffering from the disorder in question.

[0030] As used in the context of the present invention, unless otherwise specified, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of compounds and practice of methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0031] "Treatment of cognitive dysfunction" is intended to include the management and care of a patient for the purpose of combating cognitive dysfunction, and includes the administration of compounds and methods according to the present invention to reduce the signs and / or symptoms of, or eliminate, cognitive dysfunction.

[0032] The cognitive dysfunction may be associated with a sleep disorder, e.g., insomnia, a psychiatric or nervous system disorder, or another medical condition. The cognitive dysfunction may take the form of a neurocognitive disorder.

[0033] The patient may suffer from a treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two appropriate treatment courses. Particularly, the patient has not shown sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy. For example, the patient has not shown sufficient improvement after at least two appropriate drug therapy courses. These at least two previous treatment courses are particularly those administered in the current episode of the disease, for example, if the patient suffers from a disorder characterized by depressive episodes, they are administered in the current episode of depression.

[0034] As used in the context of the present invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is sought by a researcher, physician or other clinician, which biological or clinical response in humans includes alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0035] "Clinical response" includes, but is not limited to, improvements on rating scales assessing (i) cognitive function (dysfunction) or aspects of cognitive function (dysfunction), and / or (ii) psychiatric or neurological disorders or aspects of such disorders, and / or (iii) medical conditions leading to related psychiatric or neurological conditions, and / or (iv) sleep.

[0036] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, which is a measure of symptom severity, treatment response, and treatment effectiveness.

[0037] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the clinician's opinion (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0038] The CGI-Severity Scale (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in your patient?" This is rated on a 7-point scale: 1 = normal (no illness), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = very severe illness in patients.

[0039] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0040] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, clinicians compare the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of project entry [before medication was started], this patient's condition has improved greatly since treatment began: 1 = very much; 2 = very much; 3 = very minimal; 4 = unchanged from baseline; 5 = very minimal; 6 = very much worse; 7 = very much worse since treatment began."

[0041] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is a companion scale to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0042] In addition to the individual items of the scales described herein, subcombinations of the individual items may also be used to assess specific disease aspects.

[0043] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a predetermined amount of an active compound or pharmaceutical ingredient into a patient by any route. The active compound may be administered intravenously, intramuscularly, or subcutaneously.

[0044] As used in the context of the present invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosage regimen") shall mean the prescribed sequence of one or more individual administrations.

[0045] Cognitive dysfunction Cognition includes the skills required for thinking, memory, attention and problem solving.The loss or decline of these skills leads to cognitive dysfunction, and the term cognitive dysfunction is used herein to refer to the defect or impairment of any area of ​​cognition.Cognitive dysfunction can be one of the symptoms of the patient's underlying disease.

[0046] DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0047] Cognitive dysfunction can affect one or more of these domains; indeed, cognitive abilities are highly interrelated, and it is not uncommon for multiple domains to be affected.

[0048] For example, the domain of complex attention includes the subdomains of sustained attention (commonly called "concentration" or "focus"), divided attention, selective attention, and processing speed.

[0049] Thus, complex attention clearly encompasses aspects important for executive function and various cognitive tasks such as learning and memory. Cognitive control or executive function is essentially attentional, and perception and decision-making are heavily influenced by attentional abilities.

[0050] As a result, attention is not only tested in isolation, but also by cognitive control tasks / executive functions, for example. If attention is impaired, other types of cognitive abilities are likely impaired as well. Attention to a stimulus must occur before language can be understood, visual-spatial relationships recognized, information memorized, or problems solved.

[0051] Cognitive dysfunction, as the term is used herein to refer to an acquired condition and therefore represents a decline from a previously achieved level of functioning, can relate to a variety of processes.

[0052] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained with aging and may even improve over time. However, even in the absence of any pathological condition, aging leads to declines in abilities such as abstract thinking, reasoning, and decision-making. These declines are associated with fundamental age-related deficits in processing speed, attention, memory, and executive function, indicative of cognitive aging.

[0053] Independent of normal aging, cognitive dysfunction may be associated with a psychiatric or neurological disorder or some other medical condition.

[0054] Psychiatric or neurological disorders leading to or associated with cognitive dysfunction include disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; anxiety disorders, e.g., separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD). Cognitive dysfunction includes: pain disorders, such as chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from psychotropic substance use, such as substance use disorders (SUDs); psychiatric disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, and frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; and psychiatric or nervous system disorders associated with HIV, traumatic brain injury, or COVID-19 sequelae. Cognitive dysfunction can also occur in patients suffering from sleep disorders, such as insomnia.

[0055] Cognitive dysfunction also occurs in disorders that exhibit symptoms characteristic of neurocognitive disorders that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any etiologically related disorder.

[0056] Cognitive dysfunction can take the form of neurocognitive disorders.

[0057] Mild neurocognitive impairment, also known as mild cognitive impairment, is characterized by a mild decline in cognitive function from a previous level of performance in one or more cognitive domains. Affected patients still maintain independence and are able to perform daytime tasks. However, patients typically function at a suboptimal level. The implementation of compensatory strategies to maintain independence makes daily tasks more difficult.

[0058] Major neurocognitive disorders involve a significant decline in cognitive function from a previous level of performance in one or more cognitive domains. Cognitive impairment interferes with independence in daily life.

[0059] Measuring cognitive dysfunction Cognitive dysfunction can be assessed by questionnaire or neuropsychological assessment.

[0060] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a specific psychiatric or neurological disorder may include items related to cognitive function.

[0061] A neuropsychological evaluation is a process in which a person's cognitive, psychological / emotional, and behavioral functioning are comprehensively evaluated. A central part of a neuropsychological evaluation is the administration of neuropsychological tests for the formal assessment of cognitive function.

[0062] Performance on these tests is compared to norms appropriate for the patient's age, education, and social background. Tests often use a series of performance-based questions, also known as neuropsychological test batteries.

[0063] Abilities tested include language processing, visual-spatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory-perceptual function.

[0064] Common tests to assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Mini-Cog™, Screening for Cognitive Impairment in Psychosis (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

[0065] The Montreal Cognitive Assessment (MoCA) is a widely used screening test for detecting cognitive impairment. The MoCA assesses different cognitive domains, including short-term memory; visuospatial ability; executive function; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30. A score of 26 or higher is considered normal, a score of 18–25 is considered mild cognitive impairment, a score of 10–17 is considered moderate cognitive impairment, and a score below 10 is considered severe cognitive impairment.

[0066] The Mini-Mental Status Examination (MMSE) is an 11-question measure that examines five domains of cognitive function: orientation, memory, attention and calculation, recall, and language. The maximum score is 30. Raw scores may also need to be adjusted for highest level of education and age.

[0067] Herein, four cut-off levels are 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 or less means severe cognitive impairment.

[0068] When used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

[0069] The Mini-Cog™ is a short cognitive impairment screening questionnaire. The Mini-Cog™ combines a three-word recall and a clock drawing test. The clock drawing test assesses many cognitive domains that may be affected, including executive function, visuospatial ability, motor programming, and attention. One point is awarded for each of three words correctly recalled after performing the clock drawing test. A correctly drawn clock is awarded two points. A score below four indicates cognitive impairment.

[0070] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a highly regarded screening tool for assessing cognitive abilities in psychiatric patients.

[0071] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Verbal Learning Test-Delayed (VLT-D), and Processing Speed ​​Test (PST). There are three different test formats to facilitate repetition and thus 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 of less than 70 indicates cognitive dysfunction.

[0072] Cognitive dysfunction can also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of its various subtests: Trail Making Test, Part A (a test of processing speed); Brief Cognitive Assessment for Schizophrenia, Symbol Coding subtest (processing speed); Hopkins Verbal Learning Test-Revised, Immediate Recall, 3 learning trials only (verbal learning); Wechsler Memory Scale-3, Spatial Span subtest (Working Memory (Nonverbal)); Letter 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 Intelligence Test, Emotion Management Domain (social cognition); and Continuous Performance Test, Identical Pairs Version (attention / arousal).

[0073] The test battery is suitable for measuring cognitive change.

[0074] Further tests include the Verbal Recognition Memory (VRM) test, the Rapid Visual Processing (RVP) test, the Spatial Working Memory (SWM) test, and the Digit Symbol Substitution Test (DSST).

[0075] Scales for assessing mental and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders. These scales are based on tests that can be self-administered or administered by a clinician.

[0076] Scales for assessing psychiatric or nervous system disorders that may be used in accordance with the present invention include those known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0077] Treatment outcome is assessed using one or more indexes or scales at one or more time points after the course of treatment has ended.

[0078] Assessments can be performed after the acute hallucinatory experience has subsided. An appropriate time point for early assessment is typically about 2-3 hours after the last dose. Early assessments can typically be performed, for example, about 2 hours or about 3 hours after the last dose.

[0079] However, assessment of the effect on sleep disturbances can be performed earliest on the day after treatment (i.e., Day 1), so that treated patients have had the opportunity to get at least one night's sleep.

[0080] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. Evaluation will occur no earlier than 12 hours after the last dose, and in any event no later than one night after the last dose and no later than 36 hours after the last dose. Evaluation may occur after about 24 hours.

[0081] Assessment on day 7 or assessment at day 7 refers to assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment times measured in days.

[0082] If the clinical response is evaluated at an early time point (for example, 2 hours) after drug administration (for example, using one of the scales that evaluate the severity of psychiatric or nervous system disorders) based on an endpoint that is established with a longer recall period (for example, usually 7 days in MADRS), such endpoint can be reasonably modified (for example, the recall period of MADRS is changed to 2 hours, and the sleep items recorded at the baseline before drug administration are carried forward). The same applies to any other scales used herein, unless the recall period is specifically indicated.

[0083] At early time points, the considerations outlined apply because, on the one hand, the influence of the patient's condition before treatment on any scores recorded after treatment to assess clinical response should be kept as low as possible, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0084] At later time points (e.g., Day 1 or later), all items on the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0085] Mechanisms underlying cognitive dysfunction Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0086] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0087] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs). A resting-state network is a set of spatially specific brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0088] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0089] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0090] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various disease states, including certain forms of cognitive dysfunction, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0091] Resting-state fMRI is particularly advantageous when studying populations affected by cognitive dysfunction, as it allows for the examination of functional connectivity while eliminating task demands that may be confounded by underlying cognitive or motor impairments.

[0092] Cognitive processes are reflected by the functional connectivity of specific brain regions within and / or between regions located in different networks.

[0093] In particular, certain core networks, also known as "higher-order cognitive networks," are thought to be essential for most mental activities.

[0094] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), central executive network (CEN), or executive network (EN), is typically associated with executive functions, including holding and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decisions and goal-directed behavior.

[0095] Another core network is the default mode network (DMN). The DMN contains areas in the brain that are most active when a person's attention is not focused on any specific task. DMN activity is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, the integration of cognitive and emotional processing, and task-unrelated mind-wandering.

[0096] The third network is the salience network, also known as the cingulate-opercular network. This network is involved in identifying salient stimuli and events—those that other brain networks need to pay attention to. This network plays a central role in governing mental processes and behavior.

[0097] The fourth network is the dorsal attention network (DAN), which is associated with top-down, goal-directed attention processes.

[0098] The above networks do not operate independently. In fact, there are many connections between them. The cooperation between the networks is essential for their application-specific functionality.

[0099] Throughout the lifespan, brain networks undergo functional reorganization that simultaneously influences cognition. In healthy aging, age-related changes are observed in higher-level cognitive networks.

[0100] Patients suffering from cognitive dysfunction exhibit functional alterations within and / or between resting-state networks when compared to healthy, age-matched controls. Alterations are observed within and / or between the default mode network, executive network, salience network, and dorsal attention network.

[0101] Resting-state networks involved in cognition are often affected by 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 (SAD), and bipolar disorders (BD), such as bipolar I and II disorders; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive 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 (OCD); and post-traumatic stress disorder (PTSD). stress disorders (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from psychotropic substance use, such as substance use disorders (SUDs); psychiatric disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, and 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; and mental or nervous system disorders associated with HIV, traumatic brain injury, or COVID sequelae.

[0102] Resting-state networks involved in cognition are also affected by mental or neurological conditions that are the result of certain medical health conditions, as well as unspecified neurocognitive disorders.

[0103] Furthermore, resting-state networks involved in cognition are affected by sleep disorders, such as insomnia, and indeed cognitive dysfunction and sleep disorders are correlated.

[0104] Patients with sleep disorders often have poorer cognitive function, and patients with cognitive dysfunction often have sleep disorders.

[0105] Active Agent The above discussion indicates that cognitive dysfunction is characterized by several aspects and, as such, poses a significant disease burden and is amenable to appropriate treatment.

[0106] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of cognitive dysfunction and improve the condition overall.

[0107] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families, 5-HT1 through 5-HT7, with several subtypes, have been described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelic drugs" and are primarily characterized by their ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), while other effects such as sedation, narcosis, or hyperstimulation are minimal.

[0108] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0109] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and minor amine-associated receptors.

[0110] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0111] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three 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 on a self-reported manic episode after ingesting psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0112] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0113] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound to be administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0114] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from that of other hallucinogenic compounds.

[0115] 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 compared to other classical hallucinogens.

[0116] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0117] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has enhanced affinity for the 5-HT1A receptor and acts as a potent agonist. Psilocin and DMT have an increased contribution to 5-HT2A binding compared to 5-MeO-DMT, with the latter of the three compounds showing the greatest difference between their affinities for 5-HT2A and 5-HT1A. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than the other two compounds.

[0118] 5-HT1A receptor agonism has been reported to reduce impulsivity and aggression, while 5-HT2A receptor agonism may short-term increase these same traits. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0119] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes (e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD) (e.g., bipolar I disorder and bipolar II disorder), psychotic disorders (e.g., schizophrenia), or personality disorders (e.g., schizotypal personality disorder)). Patients suffering from such psychiatric or nervous system disorders do not experience treatment-emergent mania or hypomania when treated in accordance with the present invention.

[0120] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate heavy use of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD).

[0121] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0122] Furthermore, antidepressants have been reported to induce isolated hypomanic events in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. “Antidepressant-induced hypomania in treatment-resistant depression.” Journal of Psychiatric Practice 13.4 (2007):233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0123] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as a "loss of self"), often leading to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0124] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have investigated the efficacy of 5-MeO-DMT against recombinant human 5-HT7 receptors and their receptors as radioligands.3 Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM.

[0125] Thus, in addition to the 5-HT1A and 5-HT2A receptors described above, 5-MeO-DMT also interacts with the 5-HT7 receptor, at which it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0126] 5-HT7 receptors have roles in neurogenesis, synaptogenesis and dendritic spine formation, and are involved in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0127] 5-HT7 receptors are particularly expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0128] The suprachiasmatic nucleus (SNU) 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 disorders. Resting-state functional connectivity analysis in patients with sleep disorders reveals modulation of functional connectivity between the SNU and regions within the default mode network.

[0129] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe this may allow for the treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0130] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as one mediator of the pharmacological effects of 5-MeO-DMT, including "resetting" functional network connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders and / or cognitive dysfunction.

[0131] The inventors further believe that 5-MeO-DMT's binding to the 5-HT7 receptor, in addition to its binding to the 5-HT1A receptor, as two mediators of its effects, including "resetting" functional network connectivity and neuroplasticity, may also enable it to exert beneficial effects in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0132] Another characteristic of 5-MeO-DMT is its short half-life.

[0133] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0134] We investigated the pharmacokinetic properties of 5-MeO-DMT and found rapid absorption and distribution of inhaled 5-MeO-DMT, with peak concentrations and pharmacological effects observed during and immediately after administration.

[0135] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. Titrating doses as disclosed herein does not result in accumulation, and thus does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0136] The properties of 5-MeO-DMT make the compound particularly suitable for treating cognitive dysfunction, and the compound is particularly suitable for patients suffering from a medical condition leading to a psychiatric or neurological disorder or related psychiatric or neurological condition, patients suffering from a sleep disorder, e.g., insomnia, and patients suffering from an unspecified neurocognitive disorder.

[0137] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0138] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0139] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0140] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

[0141] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0142] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0143] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Even more examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0144] Methods for preparing these compounds are known in the art.

[0145] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0146] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0147] 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 metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reference can be substituted with a 5-MeO-DMT prodrug or a salt thereof.

[0148] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0149] An example of a suitable organic moiety is —C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 and each R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0150] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 , and R 4 is defined as above.

[0151] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0152] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the nitriloacetate salt (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate nitriloacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0153] Methods for preparing the prodrugs described herein are known in the art.

[0154] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0155] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0156] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenous administration, i.e., intravenous injection.

[0157] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection, and examples of excipients and vehicles for such formulations are known in the art.

[0158] Dosage regimen The present invention also provides dosage ranges, specific dosages, as well as administration regimens (administration schemes) and suitable routes of administration.

[0159] The present invention is based in part on the inventors' conclusion that the occurrence of an acute hallucinogenic peak experience following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof causally facilitates, or at least serves as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from cognitive dysfunction, particularly one or more of the aspects defined above.

[0160] Thus, achieving a peak experience more rapidly, in a greater proportion of patients, and with greater reproducibility within each individual patient compared to previously tested hallucinogens, dosing regimens, and routes of administration would result in a superior therapeutic profile.

[0161] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no attenuation or disappearance of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily) designed to increase the incidence of peak experiences and thereby enhance therapeutic efficacy. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time), induction of mania or hypomania, or a meaningless hallucinogenic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at that higher dose. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance at the patient population level.

[0162] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate and modulate the reproducibility of peak experiences, and to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the slow onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration), which may last for several days.

[0163] A patient, as defined herein, suffering from cognitive dysfunction is treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0164] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for cognitive dysfunction).

[0165] The dose of 5-MeO-DMT administered to a patient suffering from cognitive dysfunction, as defined herein, ranges from about 1 mg to about 10 mg, or any amount within this range, and is administered in the form of a dosage formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated from the stated weight of 5-MeO-DMT free base, assuming equimolar amounts are used. Specific effective amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. It should be noted that when a range, such as "about 1 mg to about 10 mg," is provided herein, the inventors contemplate all discrete values ​​within the range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0166] In a preferred embodiment, the improved method for treating a patient suffering from cognitive dysfunction with a therapeutically effective amount of 5-MeO-DMT as defined herein comprises the occurrence of a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0167] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from cognitive dysfunction with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, including a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT, for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0168] In a preferred embodiment, the improved method for treating a patient suffering from cognitive dysfunction with a therapeutically effective amount of 5-MeO-DMT as defined herein comprises more than one administration of 5-MeO-DMT.

[0169] In a preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 doses, the interval between each dose within each treatment block being at least about 1 hour and not more than about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0170] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0171] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0172] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0173] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0174] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0175] For embodiments in which the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration will be 7 mg.

[0176] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration and to a dosage selected from about 7 mg to about 9 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0177] In additional preferred embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0178] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 10 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic peak experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a hallucinogenic peak experience at an 8 mg dose, and therefore the highest dosage in the first treatment block was 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 8 mg.

[0179] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective 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.

[0180] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective 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.

[0181] Pharmaceutically acceptable salts of 5-MeO-DMT are also preferably used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0182] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0183] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0184] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0185] In accordance with the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also known as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience?; 2. How out of control was it?; and 3. How profound (i.e., meaningful) was the experience?

[0186] Treatment of cognitive dysfunction According to the present invention, cognitive dysfunction occurring in patients suffering from psychiatric or nervous system disorders or from medical conditions that lead to related psychiatric or nervous system conditions can be treated.Furthermore, cognitive dysfunction occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0187] Cognitive dysfunction in neurocognitive disorder not otherwise specified can also be treated.

[0188] In patients suffering from cognitive dysfunction associated with another condition detailed above, treatment of the cognitive dysfunction according to the present invention leads to an improvement in the condition associated with the cognitive dysfunction.

[0189] Treatment according to the present invention is carried out by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0190] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption triggers a reset of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0191] Therefore, according to the present invention, by affecting these networks by the therapies described herein, cognitive dysfunction is improved, and if the treated patient suffers from a psychiatric or nervous system disorder, the disorder is also improved.If the treated patient suffers from a medical condition that leads to a related psychiatric or nervous system condition, the related psychiatric or nervous system condition is also improved.If the treated patient suffers from a sleep disorder, such as insomnia, the sleep disorder, such as insomnia, is also improved.If the patient suffers from an unspecified neurocognitive disorder, one or more other symptoms of the disorder are also improved.

[0192] To further support the clinical application of 5-MeO-DMT in patients suffering from cognitive dysfunction, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and noted specific improvements in cognitive dysfunction that are also commonly observed in patients with other disorders.

[0193] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific medical condition, the inventors have determined that certain clinical findings from the study are relevant to the design of drugs for the treatment of other medical conditions associated with cognitive dysfunction, as described in more detail below.

[0194] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to various groups. Of interest in the context of the present invention are those receiving a single 12 mg dose and those receiving an intra-day individualized dosing regimen (IDR), which allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0195] The collected data included assessments of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, the inventors focused on the items that comprise the various scales and noted that specific subscore items, such as those related to cognitive dysfunction, may be related to other conditions in which cognitive dysfunction is based on similar changes in functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0196] Multiple patients within the pooled cohort showed significant improvement, confirming our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0197] More specifically, an aspect that can be treated by administration of 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.

[0198] The MADRS item that is particularly relevant to concentration and memory problems is "Difficulty concentrating." This item represents difficulty gathering thoughts, leading to poor concentration, and is scored on a scale of 0 to 6. If the patient has no difficulty concentrating, the score is 0. If they occasionally have difficulty gathering their thoughts, the score is 2. If they have difficulty concentrating or sustaining thoughts, which reduces their ability to read or carry on a conversation, a score of 4 is assigned. If the patient cannot read or converse without great difficulty, the score is 6.

[0199] The combined MADRS "difficulty concentrating" item score across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 30.

[0200] After 2 hours, the score decreased to 11, which corresponds to a 19-point or 63% improvement. On day 1 after treatment, the score decreased to 1, which corresponds to a 29-point or 97% improvement. On day 7 after treatment, the score decreased to 9, which corresponds to a 21-point or 70% improvement.

[0201] The baseline MADRS "difficulty concentrating" item score was 16 across all four patients in the 12 mg group.

[0202] After 2 hours, the score decreased to 7, which corresponds to a 9-point or 56% improvement. On day 1 after treatment, the score decreased to 2, which corresponds to a 14-point or 88% improvement. On day 7 after treatment, the score decreased to 3, which corresponds to a 13-point or 81% improvement.

[0203] Thus, in accordance with 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.

[0204] More specifically, 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, wherein the cognitive dysfunction is a deficiency or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. For example, the cognitive dysfunction is reduced or eliminated when it affects the cognitive domain complex attention, e.g., one or more subdomains of the cognitive domain complex attention selected from sustained attention, divided attention, selective attention, and processing speed, particularly sustained attention.

[0205] Treatment of cognitive dysfunction and sleep disorders A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder, or a medical health condition that leads to a related mental or nervous system condition. Sleep disorders affect a person's ability to function properly while awake, particularly impairing cognitive function.

[0206] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, non-REM sleep is deeper and occupies a disproportionately large portion of the time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle being allocated to REM sleep.

[0207] Normal, healthy sleep consists of different phases, as outlined above, that proceed sequentially and in a tightly regulated sequence throughout the night.

[0208] Disruption of this tight regulation leads to sleep disorders.

[0209] Common forms of sleep disorders include disorders of sleep initiation and maintenance (insomnias), disorders of excessive somnolence (hypersomnias), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial wakefulness (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0210] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have at least one daytime problem, such as difficulty falling asleep, frequent awakenings during the night and difficulty returning to sleep, waking up early in the morning, not getting enough sleep, and / or fatigue, sleepiness, mood or concentration problems, or accidents at work or while driving due to lack of sleep.

[0211] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep intoxication is also a symptom seen in patients with hypersomnia. The transition from sleep to wakefulness is difficult. Individuals experiencing sleep intoxication report confusion, disorientation, sluggishness, and repeated trips back to sleep.

[0212] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances resulting from alterations in an individual's internal circadian rhythm or from a mismatch between the circadian rhythm and desired or required work or social schedules. This dyssynchronization can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during desired wakefulness is impaired, and temporary opportunities to return to a normal sleep schedule are unsuccessful.

[0213] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) experienced by a person before falling asleep, during sleep, or during periods of arousal between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0214] Sleep-related breathing disorders are characterized by abnormal difficulty breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of the respiratory muscles and the brain (control center). One form of sleep-related breathing disorder is central sleep apnea. Central sleep apnea occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea potentially has serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to fragmented sleep due to microarousals or awakenings. This can result in excessive daytime sleepiness.

[0215] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0216] Not getting adequate sleep in adequate quantity or quality can cause personality changes, worsen existing mental disorders, and even precipitate the onset of new ones. Sleep disorders can also interfere with cognitive function and cause memory impairment. Sleep-deprived subjects may experience difficulty making decisions, irritability, problems with executive function, and slower reaction times. A recent 2019 systematic review and meta-analysis of studies investigating the relationship between insomnia and cognitive dysfunction found significant associations with impairments in memory, complex attention, attention, and executive function. Sleep deprivation can also contribute to the development of obesity, diabetes, and cardiovascular disease, negatively impacting quality of life.

[0217] Treatment for sleep disorders varies depending on the type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered primary treatments. If unsuccessful, treatments may also include medication or psychotherapy.

[0218] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve relevant therapeutic benefits.

[0219] In patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not necessarily improve the sleep disorder.

[0220] For example, sleep disorders are often associated with psychiatric disorders such as depression.However, treating depression does not necessarily improve the associated sleep disorders.Most antidepressants have been proven to affect sleep structure, but some classes of antidepressants can improve sleep, while others can cause sleep disorders.

[0221] To assess sleep, parameters such as sleep time, sleep architecture, sleep latency, and frequency and duration of wakefulness throughout the night can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-report measures (questionnaires).

[0222] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic, measuring a variety of functions throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0223] Another quantitative measure is actigraphy, in which activity sensors are worn to measure motor activity, which is then continuously recorded and used to assess sleep-wake cycles. This technology allows patients to continue their normal routine while the necessary data is recorded in a natural sleep environment.

[0224] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep over multiple test naps. An average sleep latency of approximately 10 minutes is considered normal; less than 8 minutes indicates a sleep disorder / excessive daytime sleepiness. Analysis of accompanying brain activity can aid in further diagnosis of sleep disorders.

[0225] Sleep assessment questionnaires collect ratings of components of sleep quality, such as perceived depth of sleep, difficulty waking, and feeling rested after sleep, in addition to other factors that may affect sleep quality, such as comorbid conditions and medication use. Because cognitive dysfunction and sleep disorders are associated, cognitive dysfunction is often part of the assessment.

[0226] Assessment of qualitative aspects of the sleep experience is important because sleep discomfort can often persist despite normality of quantitative measures of sleep.

[0227] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful for tracking patient progress. Self-reported sleep questionnaires completed by patients are therefore an important backbone of the assessment of sleep disorders in clinical practice.

[0228] Various sleep quality indices are known. The following indices each include examples of general questionnaires for assessing sleep, as well as questionnaires specifically for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. However, the present invention is not limited to the use of any particular index or questionnaire.

[0229] Some questionnaires rely on a recall period (recall window) of several days or weeks. This may be appropriate for diagnosing sleep disorders, but it is not always appropriate for evaluating the rapid onset of treatment effects, especially the effects after treatment. For some questionnaires, the recall period can be modified so that the score obtained reflects the period after treatment. The questionnaires specifically discussed herein for evaluating the effect of treatment on the sleep of patients suffering from certain conditions rely on a recall period that does not start earlier than the time when acute hallucinatory experiences subside after the final administration. To meet this criterion, the recall period that is usually applied is modified as necessary.

[0230] Sleep quality can generally be assessed, for example, with the Sleep Quality Scale (SQS) and Sleep-50 questionnaires.

[0231] The Sleep Quality Scale (SQS) is a comprehensive assessment tool designed to achieve a general and efficient measure suitable for assessing sleep quality in various patient and research populations. Individual questions about daytime symptoms such as attention, concentration, and memory problems (item 15, "Lack of sleep makes it hard to think," item 19, "Lack of sleep makes me make mistakes at work," item 21, "Lack of sleep makes me forgetful," and item 22, "Lack of sleep makes it hard to concentrate at work"), recovery after sleep, problems initiating and maintaining sleep, difficulty waking, and sleep satisfaction can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more acute sleep disturbances (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 during the past month or another appropriate recall period.

[0232] Successful treatment is indicated by a decrease in score.

[0233] The SLEEP-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and problems, as well as diagnostic factors such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep problems on daily functioning. For each item, respondents are provided with a scale from 1 ("not at all") to 4 ("very much") and asked to indicate how closely the statement matches their experiences over the past month or another appropriate recall period.

[0234] To diagnose a sleep disorder, not only must certain subscales (e.g., insomnia) exceed certain cutoff points, but respondents must also meet a cutoff of at least 3 or 4 ("quite a bit" or "very much," respectively) on subscales assessing the impact of sleep problems on daily functioning (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0235] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0236] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Questionnaire. Other instruments include the Insomnia Severity Index, the ESPN Sleep Disorders Questionnaire, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0237] The Pittsburgh Sleep Quality Inventory (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another suitable recall period.

[0238] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep onset time, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) time to fall asleep, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0239] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Detailed scoring instructions for the Pittsburgh Sleep Quality Questionnaire 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.

[0240] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. The cutoff for the overall score is 5, which distinguishes between individuals with and without sleep problems. A overall score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0241] When the PSQI is used to assess treatment outcome, success of treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0242] The Insomnia Severity Index (ISI) is a short questionnaire that assesses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning (item 3, "To what extent do you think your sleep problems interfere with your daily life (e.g., daytime fatigue, ability to work or perform daily chores, concentration, memory, mood, etc.)?"), how significant the respondent perceives their insomnia as compared to others, and the overall level of distress caused by sleep disturbances. Individual responses can be scored from 0 (= none) to 4 (= very). A higher total score corresponds to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 means "subthreshold insomnia," 15–21 means "moderate clinical insomnia," and 22–28 means "severe clinical insomnia" (A. Shahid et al., op. cit.). The typical recall window for ISI is two weeks, although other suitable recall windows may be used herein.

[0243] Successful treatment is indicated by (i) a reduction in score, for example a reduction of more than 7 points, especially more than 8 points, and preferably (ii) a reduction below the cut-off for clinically significant insomnia.

[0244] The Spi Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. By assessing restlessness / irritability, mental hyperactivity, consequences of insomnia, and lack of readiness to fall asleep, the SDQ is particularly concerned with beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate how frequently a particular mention of insomnia represents their experience, with 1 meaning "never true" and 5 meaning "true most of the time." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., op. cit.).

[0245] Successful treatment is indicated by a decrease in score.

[0246] The Patient-Reported Outcomes Information System (PROMIS®) Sleep Disorders Assessment Tool is a universal measure for assessing sleep disorders. This tool is available as a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and perceived difficulties associated with falling asleep and staying asleep over a 7-day period.

[0247] Each item on the measure is rated on a 5-point scale. The item raw scores are summed to obtain a total raw score. The total raw score is then converted to a standardized T-score using a conversion table.

[0248] Successful treatment is indicated by a decrease in the T-score.

[0249] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0250] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stuck in traffic. Using a scale of 0 to 3 (0 meaning "I will never fall asleep" and 3 meaning "I will likely fall asleep"), respondents rate their likelihood of falling asleep. Scoring ranges from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., op. cit.).

[0251] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0252] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a particular moment. This single-item scale requires respondents to select one of seven statements that best describes their current level of sleepiness. A scale ranging from 1 (= active, energetic mood, alert, wide alertness) to 7 (= mostly dreamy, falls asleep easily, no motivation to stay awake) is used to assess the level of sleepiness (A. Shahid et al., op. cit.).

[0253] Successful treatment is indicated by a decrease in score.

[0254] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0255] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists and rates the frequency of parasomnic behaviors, including a rating of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0256] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0257] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period may also be selected.

[0258] Successful treatment is indicated by a decrease in score.

[0259] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Scale. The 10-item questionnaire asks respondents to indicate how acutely affected they have been by the disorder during the past week using a Likert-type rating. Questions can be categorized into one of two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep disturbances, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their experience of RLS on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least severe symptoms. Total scores can range from 0 to 40. As a brief scale with good psychometric quality, this tool may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes (A. Shahid et al., op. cit.).

[0260] Treatment response can be assessed by a reduction in score.

[0261] Treatment response can be assessed by the use of quantitative measures such as polysomnography or actigraphy and / or questionnaires as described above. Depending on the sleep scale, a significant decrease or increase in the total score, or a significant decrease in the prevalence, frequency, and impact on daily functioning, respectively, indicates treatment-induced improvement of the sleep disorder.

[0262] Cognitive dysfunction in insomnia is assessed as part of a sleep assessment questionnaire, such as the SQS or ISI, as described above.

[0263] Common tests available to assess cognitive dysfunction include the Montreal Cognitive Assessment (MoCA) and the MATRICS Consensus Cognitive Battery (MCCB).

[0264] To improve our understanding of the pathophysiology and potential compensatory mechanisms involved, resting-state fMRI has been widely applied in patients with sleep disorders.

[0265] Altered resting-state networks can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders and sleep-related movement disorders.

[0266] In patients with insomnia, dysfunctional connectivity has been observed within the default mode network (DMN) and the salience network, which are involved in the detection and integration of emotional and sensory stimuli. Research has shown that these networks contain important regions that integrate emotional and physical states, and dysfunctional connectivity within these networks and / or between these networks and other brain regions may underlie patients' impaired attention, subjective distress, and sleep continuity.

[0267] For example, sleep disruption in healthy subjects leads to changes in functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these changes in brain functional connectivity bear some resemblance to vulnerability patterns in Alzheimer's disease patients.

[0268] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, distinct DMN hubs, the precuneus and medial prefrontal cortex, show significant alterations, and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0269] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm imbalances contribute to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as reactivity and alertness. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may result in alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases associated with circadian rhythm disorders.

[0270] Although it is technically difficult to perform functional brain imaging during parasomnia events, precuneus differences have been observed in disorders of wakefulness that represent non-REM parasomnias.

[0271] The precuneus is involved in analyzing and integrating visual, auditory, and sensory information, and in monitoring movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnia, the default mode network is affected.

[0272] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, have shown significant global and local connectivity deficits, particularly in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems. Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Activation of the cerebellum and thalamus, as well as the red nucleus and brainstem, can also be observed.

[0273] In many cases, the resting state networks involved in sleep regulation are also involved in cognition, and therefore, in accordance with the present invention, affecting those networks by treatment according to the present invention results in the improvement of sleep disorders and, if the treated patient suffers from cognitive dysfunction, also in the improvement of cognitive dysfunction.

[0274] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that sleep disorders can be successfully treated by administration of 5-MeO-DMT.

[0275] The TRD study, described in more detail in the Examples section below, assessed, among other things, the MADRS "Decreased Sleep" item, which reflects insomnia.

[0276] The "Decreased Sleep" item on the MADRS refers to the experience of decreased duration or depth of sleep compared to a person's normal pattern when healthy. A score of 0 is assigned if the person sleeps normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, shallow, or disrupted sleep. A score of 4 means at least 2 hours of reduced or disrupted sleep. A score of 6 means less than 2-3 hours of sleep.

[0277] Aggregate scores on the MADRS "Decreased Sleep" item across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 25. By day 1 of treatment (the earliest time point to assess the treatment's impact on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 of treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0278] The combined MADRS "Decreased Sleep" item score across all four patients in the 12 mg group had a baseline of 12. On post-treatment day 1, the score decreased to 10, corresponding to a 2-point or 17% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0279] Thus, scores for the scale item "decreased sleep," which is particularly relevant to sleep disorders, are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat sleep disorders, particularly in patients suffering from psychiatric or nervous system disorders.

[0280] Treating a patient suffering from a sleep disorder, particularly insomnia, and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, leading to improvement of the sleep disorder, particularly insomnia.

[0281] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0282] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0283] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected at least by an improvement in scores on items 15, 19, 21, and / or 22 of the Sleep Quality Scale (SQS) on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience after the last administration has subsided up to the time of assessment.

[0284] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, as reflected by an improvement in scores on items 15, 19, 21, and / or 22 of the SQS occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience following the last administration abates until the time of assessment. The reduction or elimination of cognitive dysfunction as reflected by an improvement in scores on items 15, 19, 21, and / or 22 of the SQS persists for preferably at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience following the last administration abates until the time of assessment.

[0285] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected at least by an improvement in the Insomnia Severity Index (ISI) item 3 score on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period starting no earlier than the time the acute hallucinatory experience after the last administration subsided up to the time of assessment.

[0286] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, as reflected by an improvement in the score on item 3 of the ISI, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience following the last administration abated until the time of assessment. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the score on item 3 of the ISI, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, with the recall period beginning no earlier than the time the acute hallucinatory experience following the last administration abated until the time of assessment.

[0287] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected by an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0288] The reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, as reflected by an improvement in MoCA score occurs within 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, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0289] Reduction or elimination of cognitive dysfunction in patients suffering from sleep disorders, particularly insomnia, is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores 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; 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.

[0290] The reduction or elimination of cognitive dysfunction in a patient suffering from a sleep disorder, particularly insomnia, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by 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 a patient suffering from a sleep disorder, particularly insomnia, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0291] As mentioned above, cognitive dysfunction is an important aspect in patients suffering from sleep disorder.Therefore, improving cognitive dysfunction will also lead to improving sleep disorder.Because cognitive dysfunction also affects other aspects of sleep disorder, the inventors conclude that the observed improvement of cognitive dysfunction will further contribute to the overall improvement of sleep disorder, especially insomnia.

[0292] In the case of idiopathic sleep disorders, clinical response can be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least one level. Preferably, the CGI-S score is decreased by at least two levels and / or to a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three levels and / or to a score of 0.

[0293] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, is observed on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0294] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0295] The improvement in the idiopathic sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0296] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0297] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a reduction in the CGI-I score or a score of at least "much improved" on the PGI-I, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0298] Improvement in the case of sleep disorders may also be assessed by any other measure that reflects changes in the quality or quantity of sleep as described above, for example, the Pittsburgh Sleep Quality Index (PSQI).

[0299] When the PSQI is used to assess treatment outcome, success of treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0300] Improvement in sleep disturbance, as reflected by a decrease in PSQI score, particularly a decrease to 5 or less, preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has subsided up to the time of assessment.

[0301] The improvement in sleep disturbance, as reflected by a reduction in PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience following the last administration has abated, up to the time of assessment.

[0302] Improvement in sleep disturbance, as reflected by a decrease in PSQI score, is observed on day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute hallucinatory experience after the last administration has subsided up to the time of assessment.

[0303] Cognitive dysfunction and sleep disorders, especially insomnia, are closely related to mental and nervous system disorders. Both cognitive dysfunction and sleep disorders, especially insomnia, occur in mental or nervous system disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorder; somatic symptom disorders; obsessive-compulsive 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 (OCD); psychological disorders. post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from psychotropic substance use, such as substance use disorders (SUDs); psychiatric disorders, such as schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, and 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; and mental or nervous system disorders associated with HIV, traumatic brain injury, or COVID sequelae.

[0304] Cognitive dysfunction and sleep disorders, particularly insomnia, both occur in related psychiatric or neurological conditions, medical health conditions leading to HIV, traumatic brain injury, or COVID sequelae, and neurocognitive disorder not otherwise specified.

[0305] Treatment according to the present invention improves both cognitive dysfunction and sleep disorders, particularly insomnia, as well as related psychiatric or neurological disorders (examples of which are listed above), and also improves psychiatric or neurological conditions associated with certain medical conditions described above, and also improves unspecified neurocognitive disorders.

[0306] Treatment of cognitive dysfunction and disorders of the mental and nervous system In patients suffering from cognitive dysfunction associated with a psychiatric or nervous system disorder, treatment of the cognitive dysfunction according to the present invention leads to an improvement in the condition associated with the cognitive dysfunction.

[0307] Although cognitive dysfunction can be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may suffer from, some psychiatric disorders and nervous system disorders are associated with cognitive dysfunction. In particular, the relationship between cognitive dysfunction and psychiatric disorders is bidirectional. Not only can psychiatric disorders adversely affect cognitive function, but cognitive dysfunction can also contribute to the onset, progression, and prognosis of psychiatric or nervous system disorders.

[0308] Resting-state networks often involved in cognitive dysfunction are also involved in the above conditions.

[0309] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption causes a reset of pathologically maladaptive brain connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0310] Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0311] A depressive episode is a period of depressed mood and / or loss of enjoyment in most activities.

[0312] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present during the same two-week period and representing a change from previous functioning, at least one of which is either (1) depressed mood or (2) loss of interest or enjoyment.

[0313] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0314] Cognitive dysfunction occurs in patients suffering from disorders characterized by depressive episodes and involves impairments in executive function, learning and memory, processing speed, and concentration and attention.

[0315] Cognitive dysfunction is included as a diagnostic criterion for disorders characterized by depressive episodes, and may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment.

[0316] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. Higher MADRS scores indicate more severe depression.

[0317] The items are outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, inability to feel emotions, pessimistic thoughts, and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60.

[0318] Difficulty concentrating, described as difficulty gathering thoughts manifested by an inability to concentrate, is graded from "no difficulty concentrating" (=0), "occasional difficulty gathering thoughts" (=1, 2, or 3), "difficulty concentrating and maintaining thoughts impairs ability to read or hold a conversation" (=3, 4, or 5), and "unable to read or hold a conversation without great difficulty" (=6).

[0319] The Hamilton Rating Scale for Depression (HAM-D) allows clinicians to assess the nature and severity of mood disorders in patient populations. The scale consists of 21 questions, but only the first 17 items (depressed mood, guilt, suicide, initial insomnia, nighttime insomnia, delayed insomnia, work and interest, retardation, agitation, mental anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, genital symptoms, hypochondriasis, weight loss, and insight) are used for scoring.

[0320] For most questions, scores range from 0 to 4, with 4 indicating more acute signs of depression. For some questions, the score ranges as high as 2. Total scores are tallied and can then be compared to previous scores or to predefined cutoff scores.

[0321] In the context of the item "retardation", the questionnaire assesses slowness of thought and speech, impaired concentration, and reduced motor activity.

[0322] The British Columbia Cognitive Complaints Inventory (BC-CCI) is a rapid screening self-assessment tool that assesses perceived cognitive difficulties in patients with disorders characterized specifically by depressive episodes.

[0323] The scale consists of six items assessing perceived problems in concentration, memory, expression of thoughts, word finding, slow thinking, and problem-solving difficulty over the past seven days. Item scores, ranging from 0 (not at all) to 3 (very much), are summed to obtain a total score ranging from 0 to 18. Higher scores indicate greater severity of cognitive impairment.

[0324] Cognitive dysfunction in patients suffering from a disorder characterized by a depressive episode can also be assessed using, for example, the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more component scores thereof.

[0325] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity are observed within and / or between several brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; and reduced concentration and physiological arousal.

[0326] Treating patients suffering from a disorder characterized by depressive episodes and associated cognitive dysfunction, including treatment-resistant forms of the disorder, 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 depressive episodes.

[0327] The reduction or elimination of cognitive dysfunction in patients suffering from a disorder characterized by depressive episodes is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] The reduction or elimination of cognitive dysfunction in patients suffering from a disorder characterized by depressive episodes occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0329] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0330] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the MADRS difficulty concentrating item score, occurs by 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, as reflected by an improvement in the MADRS difficulty concentrating item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0331] Reduction or elimination of cognitive dysfunction, particularly slowing, in a patient suffering from a disorder characterized by depressive episodes is reflected by at least an improvement in the score on the HAM-D slowing item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0332] The reduction or elimination of cognitive dysfunction, particularly slowing, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the HAM-D slowing item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D slowing item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0333] The reduction or elimination of cognitive dysfunction in a patient suffering from a disorder characterized by a depressive episode is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0334] The reduction or elimination of cognitive dysfunction in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0335] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by depressive episodes is reflected by an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0336] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, in patients suffering from a disorder characterized by depressive episodes, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0337] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from a disorder characterized by depressive episodes is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores 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; 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.

[0338] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in a patient suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by 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 a patient suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0339] As mentioned above, cognitive dysfunction is closely related to the disorder characterized by depressive episodes.Therefore, improving cognitive dysfunction also leads to the improvement of the disorder characterized by depressive episodes.Because cognitive dysfunction also affects other aspects of the disorder characterized by depressive episodes, the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will further contribute to the overall improvement of the disorder characterized by depressive episodes.

[0340] Improvement in the disorder characterized by depressive episodes in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0341] The improvement in the disorder characterized by depressive episodes in the patient also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes in the patient also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects a person's emotions, thoughts, and behaviors and can lead to a variety of emotional and physical problems.

[0343] Patients with MDD can suffer from treatment-resistant forms (TRD) of the disorder.

[0344] Cognitive dysfunction is common in patients with major depressive disorder (MDD) and spans multiple different cognitive domains, including memory, executive function, attention, and emotional processing.

[0345] Impairments in executive function, learning and memory, processing speed, and concentration and attention are associated with disproportionately poor outcomes in psychosocial and occupational domains. In patients with MDD, cognitive dysfunction is a major mediator of impairment, particularly through its impact on workplace performance. Attentional impairments, in particular, negatively impact daily functioning and are associated with poorer clinical outcomes.

[0346] Cognitive dysfunction is included as a diagnostic criterion for MDD, particularly impaired thinking or concentration. Associated cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention. Attention impairments adversely affect daily functioning and are associated with poor clinical outcomes. Cognitive dysfunction is disproportionately associated with poor prognosis in psychosocial and occupational domains.

[0347] Cognitive dysfunction in patients with MDD may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI), as part of the HAM-D or MADRS assessment, or using the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0348] In patients suffering from MDD, dysfunctional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, and executive control network, is observed, and functional connectivity differs significantly from that observed in healthy controls.

[0349] More specifically, alterations in functional connectivity are observed within and / or between several brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; and reduced focus and physiological arousal.

[0350] Treating patients suffering from MDD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of the MDD.

[0351] The reduction or elimination of cognitive dysfunction in patients with MDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0352] The reduction or elimination of cognitive dysfunction in patients with MDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0353] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with MDD is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0354] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with MDD, as reflected by an improvement in the MADRS difficulty concentrating item score, occurs by 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, as reflected by an improvement in the MADRS difficulty concentrating item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0355] The reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected by at least an improvement in the score on the HAM-D retardation item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0356] The reduction or elimination of cognitive dysfunction in patients with MDD, as reflected by an improvement in the HAM-D retardation item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D retardation item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0357] The reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0358] The reduction or elimination of cognitive dysfunction in patients with MDD, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] The reduction or elimination of cognitive dysfunction in a patient suffering from MDD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0360] The reduction or elimination of cognitive dysfunction in patients with MDD, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0361] Reduction or elimination of cognitive dysfunction in a patient with MDD is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0362] The reduction or elimination of cognitive dysfunction in patients with MDD, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0363] As mentioned above, cognitive dysfunction is closely related to MDD.Therefore, improving cognitive dysfunction will also lead to the improvement of MDD.Because cognitive dysfunction also affects other aspects of MDD, the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will further contribute to the overall improvement of MDD.

[0364] Improvement in MDD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0365] Improvement in MDD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, occurs by 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 score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks after delivery. Over 50% of women may experience a short-term period of depressed or tearful mood after giving birth, but some women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0367] Patients with PPD can suffer from treatment-resistant forms of the disorder.

[0368] PPD also affects cognition, with many people with PPD frequently complaining of memory problems that interfere with daily activities.

[0369] Depression during the postpartum period not only affects the mother's overall health, but also how she interacts with her child and how the child develops.

[0370] Cognitive dysfunction in patients with PPD may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI), as part of the HAM-D or MADRS assessment, or using the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0371] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with dysfunctional resting-state network connectivity, e.g., within and / or between the default mode network and the frontoparietal network.

[0372] Treating patients suffering from PPD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of the PPD.

[0373] The reduction or elimination of cognitive dysfunction in patients with PPD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] The reduction or elimination of cognitive dysfunction in patients with PPD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0375] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with PPD is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0376] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with PPD, as reflected by an improvement in the MADRS difficulty concentrating item score, occurs by 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, as reflected by an improvement in the MADRS difficulty concentrating item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0377] The reduction or elimination of cognitive dysfunction in patients with PPD is reflected by at least an improvement in the score on the HAM-D retardation item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0378] The reduction or elimination of cognitive dysfunction in patients with PPD, as reflected by an improvement in the HAM-D retardation item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D retardation item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0379] The reduction or elimination of cognitive dysfunction in patients with PPD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0380] The reduction or elimination of cognitive dysfunction in patients with PPD, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0381] The reduction or elimination of cognitive dysfunction in patients with PPD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0382] The reduction or elimination of cognitive dysfunction in patients with PPD, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0383] Reduction or elimination of cognitive dysfunction in patients with PPD is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0384] The reduction or elimination of cognitive dysfunction in patients with PPD, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0385] As mentioned above, cognitive dysfunction is closely related to PPD.Therefore, improving cognitive dysfunction will also lead to the improvement of PPD.Because cognitive dysfunction also affects other aspects of PPD, the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will further contribute to the overall improvement of PPD.

[0386] Improvement in PPD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0387] The improvement in PPD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in PPD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0388] Cognitive dysfunction further impairs maternal function.

[0389] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index is designed to measure functioning during the year following childbirth. The BIMF is a 20-item self-report scale. Each item is assigned a score of 0 to 6, with a maximum total score of 120. A higher score indicates better maternal functioning.

[0390] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-child interaction, maternal emotional well-being, social support, control, and adaptation.

[0391] A BIMF of 95 or less is considered herein to represent a mild impairment of maternal functioning, a score of 80 or less is considered herein to represent a severe impairment of maternal functioning, and a score of 65 or less is considered herein to represent a severe impairment of maternal functioning.

[0392] The inventors determined that elevated scores on the MADRS item "Difficulty concentrating" negatively impact maternal functioning (maternal competence regarding interactions with infant(s) and maternal self-care).

[0393] An increase in the score on the MADRS item "Difficulty concentrating" impairs the care and management of the infant. Conversely, an improvement on this MADRS item translates to an improvement in maternal functioning, particularly in the BIMF functional domain of infant care and / or management.

[0394] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in cognitive function, particularly reduction or elimination of concentration difficulties.

[0395] We further conclude that reduction or elimination of concentration difficulties by treating PPD patients leads not only to a reduction in MADRS total scores but also to improved maternal functioning as reflected by an increase in BIMF scores.

[0396] The BIMF total score improves by 10% or more, preferably 20% or more.

[0397] Improvement in maternal function in patients with PPD is reflected by an improvement in the BIMF total score on at least days 7; 14; and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0398] Improvement in maternal function in patients with PPD, as reflected by an improvement in the BIMF total score, occurs by about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0399] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. Persistent depressive disorder is diagnosed when depression is present most days of the day for at least two years, with each symptom-free interval lasting less than two months.

[0400] During depression, two or more of the following must be present: 1. Feeling hopeless; 2. Low energy or fatigue; 3. Low self-esteem; 4. Decreased sleep (insomnia) or increased sleep (hypersomnia); 5. Poor appetite or overeating; 6. Difficulty making decisions or poor concentration.

[0401] Patients suffering from persistent depressive disorder may suffer from treatment-resistant forms of the disorder.

[0402] Cognitive dysfunction is common in patients with persistent depressive disorder and spans several different cognitive domains, including memory, executive function, attention, and emotional processing.

[0403] Impairments in executive function, learning and memory, processing speed, and concentration and attention are associated with disproportionately poor outcomes in psychosocial and occupational domains. In patients with persistent depressive disorder, cognitive dysfunction is a major mediator of impairment, particularly through its impact on workplace performance. Attentional impairments, in particular, negatively impact daily functioning and are associated with poorer clinical outcomes.

[0404] Cognitive dysfunction is included as a diagnostic criterion for persistent depressive disorder, especially the decline of thinking or concentration ability.Related cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention.Attention disorders have a negative impact on daily functioning and are associated with poor clinical outcomes.Cognitive dysfunction is disproportionately associated with poor prognosis in psychosocial and occupational areas.

[0405] Cognitive dysfunction in patients with persistent depressive disorder may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI), as part of the HAM-D or MADRS assessment, or using the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0406] In patients suffering from persistent depressive disorder, altered functional connectivity has been observed within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; and reduced focus and physiological arousal. Dysfunctional connectivity and regulation has been observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0407] Treating 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.

[0408] The reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0409] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from persistent depressive disorder is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0411] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from persistent depressive disorder, as reflected by an improvement in the MADRS difficulty concentrating item score, occurs by 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, as reflected by an improvement in the MADRS difficulty concentrating item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0412] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder is reflected by at least an improvement in the score on the HAM-D delay item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0413] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder, as reflected by an improvement in the HAM-D delay item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D delay item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0414] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0415] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0416] The reduction or elimination of cognitive dysfunction in patients suffering from persistent depressive disorder is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0417] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0418] Reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0419] The reduction or elimination of cognitive dysfunction in patients with persistent depressive disorder, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0420] As mentioned above, cognitive dysfunction is closely related to persistent depressive disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of persistent depressive disorder.Because cognitive dysfunction also affects other aspects of persistent depressive disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will further contribute to the overall improvement of persistent depressive disorder.

[0421] Improvement in persistent depressive disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0422] The improvement in persistent depressive disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in persistent depressive disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0423] Seasonal affective disorder is a mood disorder with a seasonal pattern; symptoms often begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0424] Patients suffering from seasonal affective disorder may suffer from treatment-resistant forms of the disorder.

[0425] The cognitive dysfunction associated with seasonal affective disorder may affect concentration, perception, attention, or memory.Importantly, in patients with seasonal affective disorder, cognition declines not only in winter but also in summer.Compared with controls, patients with seasonal affective disorder show significant impairments that are not dependent on season in tasks that measure working memory, cognitive processing speed, and motor speed.

[0426] Cognitive dysfunction in patients with seasonal affective disorder may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI), as part of the HAM-D or MADRS assessment, or using the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0427] Altered functional connectivity within and / or between resting-state networks associated with visual, sensorimotor, and attentional processing has been detected in patients with seasonal affective disorder compared with healthy controls. For example, attention deficits are a common symptom in patients with seasonal affective disorder. Rs-fMRI reveals selective changes in functional connectivity in brain regions associated with attentional processing.

[0428] Treating patients suffering from seasonal affective disorder and associated cognitive dysfunction, including treatment-resistant forms of the disorder, 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.

[0429] The reduction or elimination of cognitive dysfunction in patients with seasonal affective disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0430] The reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0431] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0432] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients suffering from seasonal affective disorder, as reflected by an improvement in the score on the MADRS difficulty concentrating item, occurs by 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, as reflected by an improvement in the score on the MADRS difficulty concentrating item, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0433] The reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the score on the HAM-D delay item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0434] The reduction or elimination of cognitive dysfunction in patients with seasonal affective disorder, as reflected by an improvement in the HAM-D delay item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D delay item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0435] The reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0436] The reduction or elimination of cognitive dysfunction in patients with seasonal affective disorder, as reflected by an improvement in SCIP score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0437] The reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0438] The reduction or elimination of cognitive dysfunction in patients with seasonal affective disorder, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0439] Reduction or elimination of cognitive dysfunction in a patient suffering from seasonal affective disorder is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0440] The reduction or elimination of cognitive dysfunction in patients with seasonal affective disorder, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0441] As mentioned above, cognitive dysfunction is closely related to seasonal affective disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of seasonal affective disorder.Because cognitive dysfunction also affects other aspects of seasonal affective disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulty, will further contribute to the overall improvement of seasonal affective disorder.

[0442] Improvement in seasonal affective disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0443] The improvement in seasonal affective disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). Bipolar disorder is a chronic, relapsing illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0445] If there has been at least one manic episode with or without a depressive episode, BD is classified as bipolar I disorder. If there has been at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode, BD is classified as bipolar II disorder. If these symptoms are due to drugs or medical problems, it is not diagnosed as bipolar disorder.

[0446] Patients suffering from BD, including bipolar I disorder and bipolar II disorder, can suffer from treatment-resistant forms of the disorder.

[0447] In BD, including bipolar I disorder and bipolar II disorder, cognitive impairment is present throughout acute emotional states and also during periods of normal mood between these states.

[0448] Cognitive impairment in BD is seen across multiple domains, particularly in language and working memory, attention, and executive function.

[0449] Cognitive dysfunction in patients with BD may be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI), as part of the HAM-D or MADRS assessment, or using the Screening for Cognitive Impairment in Psychosis (SCIP), the Montreal Cognitive Assessment (MoCA), or the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores.

[0450] The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated for clinical use by trained raters. BDRS items are based on a clinical interview and assess the severity of depressive and / or mixed symptoms exhibited by the patient during the current and past few days. If there is a discrepancy between current and past few days' symptoms, the current symptoms should be reflected in the assessment. The scale contains 20 questions, with a maximum possible score of 60. Higher scores indicate greater severity.

[0451] Questions address depressed mood, sleep disturbances, appetite disturbances, decreased social engagement, decreased energy and activity, decreased motivation, impaired concentration and memory, anxiety, anhedonia, flat affect, feelings of worthlessness, feelings of helplessness and hopelessness, suicidal thoughts, feelings of guilt, psychotic symptoms, irritability, lability, increased motor impulsivity, increased speech, and agitation.

[0452] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3.

[0453] Concentration and memory impairment is scored as 0 if there is no subjectively reported impairment in attention, concentration, or memory and resulting impairment; 1 (mild) if there is slight impairment in attention, concentration, or memory and no impairment; 2 (moderate) if there is significant impairment in attention, concentration, or memory and some impairment; and 3 (severe) if there is marked impairment in concentration or memory and considerable impairment (e.g., inability to read or watch television).

[0454] Patients suffering from bipolar disorder exhibit characteristic abnormal intrinsic organization and interconnectivity of resting-state networks.

[0455] Compared to healthy controls, resting-state functional magnetic resonance imaging studies showed altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network.

[0456] Treating patients suffering from BD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of BD.

[0457] The reduction or elimination of cognitive dysfunction in patients with BD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0458] The reduction or elimination of cognitive dysfunction in patients with BD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0459] Reduction or elimination of cognitive dysfunction, particularly concentration and memory impairment, in patients with BD is reflected by at least an improvement in scores on the BDRS concentration and memory impairment items at about 2 hours, day 1 (e.g., about 24 hours), day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0460] Reduction or elimination of cognitive dysfunction, particularly concentration and memory impairment, in patients with BD, as reflected by improvement in BDRS concentration and memory impairment item scores occurs by approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0461] The reduction or elimination of cognitive dysfunction, particularly concentration and memory impairment, as reflected by improvements in BDRS concentration and memory impairment scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0462] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with BD is reflected by at least an improvement in the difficulty concentrating score on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0463] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating, in patients with BD, as reflected by an improvement in the MADRS difficulty concentrating item score, occurs by 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, as reflected by an improvement in the MADRS difficulty concentrating item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0464] Reduction or elimination of cognitive dysfunction in patients with BD is reflected by at least an improvement in the score on the HAM-D retardation item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0465] The reduction or elimination of cognitive dysfunction in patients with BD, as reflected by an improvement in the HAM-D delay item score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the HAM-D delay item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0466] The reduction or elimination of cognitive dysfunction in patients with BD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0467] The reduction or elimination of cognitive dysfunction in patients with BD, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0468] The reduction or elimination of cognitive dysfunction in patients with BD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0469] The reduction or elimination of cognitive dysfunction in patients with BD, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0470] Reduction or elimination of cognitive dysfunction in patients with BD is reflected by an improvement in the MATRICS Consensus Cognitive Battery (MCCB) score or one or more of its component scores at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0471] The reduction or elimination of cognitive dysfunction in patients with BD, as reflected by an improvement in the MCCB score or one or more of its component scores, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MCCB score or one or more of its component scores, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] As mentioned above, cognitive dysfunction is closely related to BD. Therefore, improving cognitive dysfunction will also lead to improvement of BD. Because cognitive dysfunction also affects other aspects of BD, the inventors conclude that improving cognitive dysfunction, especially reducing or eliminating difficulty in concentration, will further contribute to the overall improvement of BD.

[0473] Improvement in BD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0474] Improvement in BD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include feelings of tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system associated with preparation for an anticipated event or situation that is perceived as threatening.

[0476] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorders.

[0477] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases.

[0478] The Hamilton Anxiety Rating Scale (HAM-A) is used to measure the severity of anxiety symptoms in various anxiety disorders (panic, phobic, and generalized anxiety). This scale consists of 14 items, each defined by a set of symptoms, measuring both mental anxiety (mental agitation and distress) and somatic anxiety (physical problems related to anxiety). Item 5 is "intellectual," defined as "difficulty concentrating, poor memory." Each item is scored on a scale from 0 (absent) to 4 (severe), with a total score ranging from 0 to 56, with scores below 17 indicating mild severity, 18 to 24 indicating mild to moderate severity, and 25 to 30 indicating moderate to severe severity.

[0479] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0480] Anxiety disorders are studied by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). Additional networks affected by these disorders are the salience network (SN) and the somatomotor network (SMN). The resting balance within and / or between each of these networks (e.g., SMN and SN) relative to the DMN may be abnormal in different anxiety disorders.

[0481] Treating patients suffering from anxiety disorders and associated cognitive dysfunction, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the anxiety disorder.

[0482] The reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0483] The reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in a patient suffering from an anxiety disorder is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from an anxiety disorder, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0486] The reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] The reduction or elimination of cognitive dysfunction in patients with anxiety disorders, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] The reduction or elimination of cognitive dysfunction in a patient suffering from an anxiety disorder is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] The reduction or elimination of cognitive dysfunction in patients suffering from anxiety disorders, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0490] As mentioned above, cognitive dysfunction is closely related to anxiety disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of anxiety disorder.Because cognitive dysfunction also affects other aspects of anxiety disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulty and memory decline, will further contribute to the overall improvement of anxiety disorder.

[0491] Improvement in anxiety disorders in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0492] The improvement in the anxiety disorder in the patient who also suffers from an associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the anxiety disorder in the patient who also suffers from an associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0493] Separation anxiety disorder is characterized by excessive anxiety about separation from home and / or from people for whom the patient has strong feelings.

[0494] Separation situations can be very distressing for sufferers, and they may find it difficult to attend school or work due to the separation. Patients suffering from separation anxiety disorder may also have excessive anxiety about unwanted events happening to important people in their lives, such as family members.

[0495] Patients suffering from separation anxiety disorder may suffer from treatment-resistant forms of the disorder.

[0496] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases.

[0497] Assessment of cognitive dysfunction is part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychosis (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0498] Functional magnetic resonance imaging in individuals suffering from separation anxiety disorder reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0499] Treating patients suffering from separation anxiety disorder and associated cognitive dysfunction, including treatment-resistant forms of the disorder, 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.

[0500] The reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0501] The reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from separation anxiety disorder is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0503] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from separation anxiety disorder, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0504] The reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0505] The reduction or elimination of cognitive dysfunction in patients with separation anxiety disorder, as reflected by an improvement in SCIP score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0506] The reduction or elimination of cognitive dysfunction in a patient suffering from separation anxiety disorder is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] The reduction or elimination of cognitive dysfunction in patients with separation anxiety disorder, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0508] As mentioned above, cognitive dysfunction is closely related to separation anxiety disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of separation anxiety disorder.Because cognitive dysfunction also affects other aspects of separation anxiety disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulty and memory decline, will further contribute to the overall improvement of separation anxiety disorder.

[0509] Improvement in separation anxiety disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0510] Improvement in separation anxiety disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, occurs by 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 score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0511] Agoraphobia is the fear of situations or places that can cause panic, feelings of being trapped, helpless, or embarrassed.

[0512] Patients suffering from agoraphobia may have difficulty leaving the house. The idea of ​​leaving the house can cause significant anxiety, even to the point of avoidance. Fear of crowds, travel, elevators, movie theaters, malls, etc. can pose significant challenges.

[0513] Patients with agoraphobia may also have recurrent panic attacks.

[0514] Patients suffering from agoraphobia may suffer from treatment-resistant forms of the disorder.

[0515] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases.

[0516] Assessment of cognitive dysfunction is part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychosis (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0517] Functional magnetic resonance imaging in individuals suffering from agoraphobia reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0518] Treating patients suffering from agoraphobia and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of agoraphobia.

[0519] The reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0520] The reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0521] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in a patient suffering from agoraphobia is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0522] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from agoraphobia, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0523] The reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0524] The reduction or elimination of cognitive dysfunction in patients with agoraphobia, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] The reduction or elimination of cognitive dysfunction in a patient suffering from agoraphobia is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0526] The reduction or elimination of cognitive dysfunction in patients with agoraphobia, as reflected by an improvement in the MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0527] As mentioned above, cognitive dysfunction is closely related to agoraphobia. Therefore, improving cognitive dysfunction will also lead to the improvement of agoraphobia. Because cognitive dysfunction also affects other aspects of agoraphobia, the inventors conclude that improving cognitive dysfunction, especially reducing or eliminating concentration difficulties and memory decline, will further contribute to the overall improvement of agoraphobia.

[0528] Improvement in agoraphobia in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0529] Improvement in agoraphobia in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by 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 reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0530] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and uncontrollable worry about a wide range of situations and problems. People with GAD may anticipate difficulties and worry excessively about money, health, family, work, or other problems.

[0531] Generalized anxiety disorder is diagnosed when an individual experiences exaggerated and persistent worry about everyday challenges and perceived threats. Patients with GAD typically experience excessive fear that can last for months or years.

[0532] GAD interferes with social, occupational, or other important areas of functioning.

[0533] Patients with GAD can suffer from treatment-resistant forms of the disorder.

[0534] Patients with GAD report at least three of the following six symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbances.

[0535] Elderly patients with GAD exhibit poorer cognitive function, particularly short-term memory, when compared with non-anxious age-matched individuals.

[0536] Impairments in general cognition as well as inductive reasoning and inhibition have been found to be risk factors for the development of GAD in later life.

[0537] Difficulty concentrating is thought to be one mechanism by which worry increases its clinical severity. Difficulty concentrating causes significant distress and impairment in role functioning.

[0538] Assessment of cognitive dysfunction is part of the DSM-5 Generalized Anxiety Disorder Questionnaire and the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychosis (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0539] Patients with GAD also show altered functional connectivity, particularly within the default mode network.

[0540] Treating patients suffering from GAD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and leads to improvement of GAD.

[0541] The reduction or elimination of cognitive dysfunction in patients with GAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0542] The reduction or elimination of cognitive dysfunction in patients with GAD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0543] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD, as reflected by an improvement in MoCA score occurs by 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 memory decline, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0548] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with GAD, as reflected by an improvement in SCIP score occurs by 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 memory decline, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0549] As mentioned above, cognitive dysfunction is closely related to GAD.Therefore, improving cognitive dysfunction will also lead to improving GAD.Since cognitive dysfunction also affects other aspects of GAD, the inventors conclude that improving cognitive dysfunction, especially reducing or eliminating concentration difficulties and memory decline, will further contribute to the overall improvement of GAD.

[0550] Improvement in GAD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0551] The improvement in GAD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in GAD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0552] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety.

[0553] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations, which often leads to avoidance of social situations and can cause impairment in school, work, or relationships.

[0554] Patients with SAD may suffer from treatment-resistant forms of the disorder.

[0555] Cognitive dysfunction is also associated with SAD.

[0556] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases.

[0557] Assessment of cognitive dysfunction is part of the Hamilton Anxiety Rating Scale (HAM-A). The Screening for Cognitive Impairment in Psychosis (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0558] Anxiety disorders exhibit 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 primarily present in the DMN and SN.

[0559] Treating patients suffering from SAD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of SAD.

[0560] The reduction or elimination of cognitive dysfunction in patients with SAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] The reduction or elimination of cognitive dysfunction in patients with SAD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0563] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0564] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0565] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD, as reflected by an improvement in MoCA score occurs by 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 memory decline, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0566] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0567] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with SAD, as reflected by an improvement in SCIP score occurs by 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 memory decline, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0568] As mentioned above, cognitive dysfunction is closely related to SAD.Therefore, improving cognitive dysfunction will also lead to the improvement of SAD.Because cognitive dysfunction also affects other aspects of SAD, the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty and memory decline, will further contribute to the overall improvement of SAD.

[0569] Improvement in SAD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0570] The improvement in SAD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in SAD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0571] Patients with panic disorder experience spontaneous panic attacks, which are sudden onsets of intense fear or discomfort that peak within minutes.

[0572] Panic attacks are characterized by many somatic anxiety symptoms, including sweating, trembling, shaking, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0573] Additionally, the disorder can often be characterized by anxiety about future panic attacks, and patients can become preoccupied with fear of recurrent attacks.

[0574] Patients suffering from panic disorder may suffer from treatment-resistant forms of the disorder.

[0575] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases. Patients with panic disorder have been found to have abnormal early processing of stimuli, manifested as increased startle responses and decreased habituation, when compared with non-panic disorder individuals.

[0576] Impaired memory function is a characteristic observed in patients with panic disorder.

[0577] 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.

[0578] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0579] Patients with panic disorder exhibit altered functional connectivity within and / or between the default mode network and the somatomotor network.

[0580] Functional magnetic resonance imaging of anxiety disorders reveals abnormalities in the default mode network (DMN), salience network (SN), and somatomotor / sensorimotor network (SMN). The resting-state balance within and / or between each of these networks (e.g., SMN and SN) relative to the DMN may be abnormal in different anxiety disorders.

[0581] Treating patients suffering from panic disorder and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the panic disorder.

[0582] The reduction or elimination of cognitive dysfunction in patients suffering from panic disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] The reduction or elimination of cognitive dysfunction in patients suffering from panic disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0585] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0586] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0587] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder, as reflected by an improvement in MoCA score, occurs by 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 memory decline, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0588] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0589] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from panic disorder, as reflected by an improvement in SCIP score, occurs by 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 memory decline, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] As mentioned above, cognitive dysfunction is closely related to panic disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of PD.Because cognitive dysfunction also affects other aspects of panic disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulty and memory decline, will further contribute to the overall improvement of panic disorder.

[0591] Improvement in panic disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0592] Improvement in panic disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in panic disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0593] A phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation.

[0594] Patients suffering from phobias experience extreme anxiety when anticipating exposure or when exposed to the phobic stimulus. There are animal-type (spiders, snakes, dogs) phobias, environmental-type (tornadoes, heights, water, fire) phobias, blood-injection-type (needles, medical procedures) phobias, situational-type (flying in an airplane, confined spaces) phobias, and other types of phobias (phobias that do not fit into any of the above categories).

[0595] Phobias typically result in a rapid onset of fear, usually present for more than six months. Patients make significant efforts to avoid the feared stimulus. The fear and avoidance cause significant distress and / or impairment in occupational, academic, or social functioning.

[0596] Patients suffering from phobias may suffer from treatment-resistant forms of the disorder.

[0597] Cognitive dysfunction in phobias can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A).

[0598] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0599] Abnormalities tend to normalize with successful treatment, for example, cognitive-behavioral treatment.

[0600] In individuals with specific phobias, the amygdala, anterior cingulate cortex (ACC), and insular cortex all appear to be hyperresponsive to phobia-related stimuli in specific phobias. For example, functional neuroimaging studies have identified the dorsal portion of the anterior cingulate cortex (dACC), which is part of the salience network, as hyperresponsive to phobia-related stimuli or the anticipation of such stimuli.

[0601] Treating patients suffering from phobias and associated cognitive dysfunction, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and results in improvement of the phobia.

[0602] The reduction or elimination of cognitive dysfunction in a patient suffering from a phobia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] The reduction or elimination of cognitive dysfunction in a patient suffering from a phobia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in a patient suffering from a phobia is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0605] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from phobia, as reflected by an improvement in the HAM-A "Intellectual" item score occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0606] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in a patient suffering from a phobia is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0607] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from phobia, as reflected by an improvement in MoCA score, occurs by 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 memory decline, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0608] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in a patient suffering from a phobia is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0609] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from phobia, as reflected by an improvement in SCIP score, occurs by 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 memory decline, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] As mentioned above, cognitive dysfunction is closely related to phobia. Therefore, improving cognitive dysfunction will also lead to improvement of phobia. Because cognitive dysfunction also affects other aspects of phobia, the inventors conclude that improving cognitive dysfunction, especially reducing or eliminating concentration difficulties and memory decline, will further contribute to the overall improvement of phobia.

[0611] Improvement in phobia in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0612] The improvement in phobia in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in phobia in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0613] Substance / drug-induced anxiety disorder is an anxiety disorder in which anxiety or panic occurs after alcohol, drug abuse, or substance use or exposure to a toxin. Substance / drug-induced anxiety disorder results in prominent symptoms of panic or anxiety and can occur during the intoxication or withdrawal phase of substance or drug use.

[0614] The disturbance causes clinically significant difficulty or impairment in social, occupational, or other important areas of functioning.

[0615] While taking the substance or drug, or within a short time afterwards, an individual suffering from substance / drug-induced anxiety disorder may feel nervous and anxious, experience symptoms of negative thinking, may have problems concentrating or memory, may feel out of control, psychotic, or fear of death, may lose weight due to gastrointestinal problems, may have chills, hot flashes, sweating, tremors, numbness, or palpitations, difficulty breathing, difficulty swallowing, or chest pain.

[0616] Patients suffering from substance / drug-induced anxiety disorder may suffer from treatment-resistant forms of the disorder.

[0617] Several domains of cognitive function are dysregulated across anxiety states and disorders more broadly, including spatial working memory, executive function, and attentional biases.

[0618] 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.

[0619] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0620] Functional magnetic resonance imaging in individuals suffering from substance / drug-induced anxiety disorders reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0621] Treating patients suffering from substance / drug-induced anxiety disorder and associated cognitive dysfunction, including treatment-resistant forms of the disorder, 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.

[0622] The reduction or elimination of cognitive dysfunction in patients suffering from substance / drug-induced anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0623] The reduction or elimination of cognitive dysfunction in patients with substance / drug-induced anxiety disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0624] Reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from substance / drug-induced anxiety disorder is reflected by at least an improvement in the score on the HAM-A "Intellectual" item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0625] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in the HAM-A "Intellectual" item score, occurs by 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 memory decline, as reflected by an improvement in the HAM-A "Intellectual" item score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0626] The reduction or elimination of cognitive dysfunction in a patient suffering from a substance / drug-induced anxiety disorder is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychosis (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0627] The reduction or elimination of cognitive dysfunction in patients suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] The reduction or elimination of cognitive dysfunction in a patient suffering from a substance / drug-induced anxiety disorder is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] The reduction or elimination of cognitive dysfunction in patients suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0630] As mentioned above, cognitive dysfunction is closely related to substance / drug-induced anxiety disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of substance / drug-induced anxiety disorder.Since cognitive dysfunction also affects other aspects of substance / drug-induced anxiety disorder, the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulties and memory decline, will further contribute to the overall improvement of substance / drug-induced anxiety disorder.

[0631] Improvement in substance / drug-induced anxiety disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0632] Improvement in substance / drug-induced anxiety disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in substance / drug-induced anxiety disorder in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] Somatic symptom disorder Somatic symptom disorder is a mental disorder diagnosed when a person is significantly focused on physical symptoms, such as pain, weakness, or shortness of breath, to the point that they cause significant distress and / or impairment and / or disruption to daily life. Illness-related emotions and behaviors are exaggerated or exaggerated.

[0634] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorders, if the impairment is significant and persistent, the impairment can lead to disability.

[0635] In somatic symptom disorder (SSD), cognitive dysfunction is associated with perceptual distortions that exaggerate bodily sensations. Attention is focused on bodily symptoms, normal bodily sensations are attributed to physical illness (perhaps with the worst possible interpretation), worries about illness occur, and fears that physical activity may cause bodily injury. Associated behavioral features may include repeated checking of the body for abnormalities, repeated seeking of medical support and stability, and avoidance of physical activity.

[0636] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptoms - Adult scale. This scale includes 15 somatic symptoms. Respondents are asked to rate the severity of their personal somatic symptoms over the past seven days. Scores range from "0" ("not at all bothersome"), "1" ("somewhat bothersome"), to "2" ("very bothersome"). Total scores can range from 0 to 30, with higher scores indicating greater somatic symptom severity. Cutoff scores of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0637] Alternatively, the Somatic Symptom Disorder-B Criterion Scale (SSD-12) can be used. Cognitive, emotional, and behavioral criteria are measured by 12 items, with total item scores ranging from 0 to 4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = very often). Ratings are summed to create a simple total score, which can vary from 0 to 48 points. Attention shifts are considered with the items "Because of my physical problems, I have difficulty concentrating on other things" or "My physical problems take up most of my day."

[0638] Additionally, cognitive dysfunction in individuals with SSD can be assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA).

[0639] Functional brain connectivity analysis reveals alterations within and / or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Alterations are identified within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor network. Somatic symptom disorder may be associated with altered sensory discrimination processing of somatic symptoms, which is influenced by emotional processing.

[0640] Treating a patient 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 leads to improvement of the somatic symptom disorder.

[0641] The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] The reduction or elimination of cognitive dysfunction in a patient suffering from a somatic symptom disorder occurs within 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 a patient suffering from a somatic symptom disorder preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] The reduction or elimination of cognitive dysfunction in a patient suffering from somatic symptom disorder is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0644] The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] The reduction or elimination of cognitive dysfunction in a patient suffering from somatic symptom disorder is reflected by at least an improvement in Mini-Mental Status Examination (MMSE) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] The reduction or elimination of cognitive dysfunction in patients suffering from somatic symptom disorder, as reflected by an improvement in MMSE score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MMSE score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] As mentioned above, cognitive dysfunction and somatic symptom disorder are closely related.Therefore, improving cognitive dysfunction will also lead to improving somatic symptom disorder.Since cognitive dysfunction also affects other aspects of somatic symptom disorder, the inventors conclude that improving cognitive function will further contribute to the overall improvement of somatic symptom disorder.

[0648] Improvement in somatic symptom impairment in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0649] The improvement in somatic symptom disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in somatic symptom disorder in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0650] Obsessive-Compulsive and Related Disorders Obsessive-compulsive disorder (OCD) is a mental illness that causes unwanted recurring thoughts or sensations (obsessions) or urges to do something repeatedly (compulsions). Patients may suffer from both obsessions and compulsions.

[0651] Patients with OCD can suffer from treatment-resistant forms of the disorder.

[0652] Patients with OCD exhibit widespread impairments across multiple cognitive domains, including memory, attention, executive function, and language. Patients may have reduced cognitive flexibility during task performance as cognitive resources are engaged in obsessions.

[0653] Cognitive dysfunction can be assessed by the 13-item Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13), originally developed to explore cognitive difficulties in OCD, which provides a measure of neurocognitive-related dysfunction and can be used to measure the impact of OCD on daily functioning.

[0654] The CAIOC-13 examines 13 cognitive domains related to psychosocial impairments in OCD: (1) reading difficulties, (2) doubt, (3) apathy, (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) compulsivity.

[0655] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0656] Underlying neurobiological differences account for various forms of cognitive dysfunction in OCD patients compared to age-matched healthy individuals. Neuroimaging studies using functional magnetic resonance imaging in patients with OCD have shown altered functional connectivity within and / or between the frontoparietal network, salience network, and default mode network.

[0657] Treating patients suffering from OCD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and leads to improvement of the OCD.

[0658] The reduction or elimination of cognitive dysfunction in a patient suffering from OCD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] The reduction or elimination of cognitive dysfunction in a patient suffering from OCD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] The reduction or elimination of cognitive dysfunction in a patient suffering from OCD is reflected by at least an improvement in the CAIOC-13 score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0661] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with OCD, as reflected by an improvement in CAIOC-13 score, occurs by 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 memory decline, as reflected by an improvement in CAIOC-13 score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0662] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients suffering from OCD is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) scores about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0663] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with OCD, as reflected by an improvement in MoCA score occurs by 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 memory decline, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0664] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with OCD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] The reduction or elimination of cognitive dysfunction, particularly difficulty concentrating and memory decline, in patients with OCD, as reflected by an improvement in SCIP score occurs by 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 memory decline, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0666] As mentioned above, cognitive dysfunction is closely related to OCD.Therefore, improving cognitive dysfunction will also lead to the improvement of OCD.Since cognitive dysfunction also affects other aspects of OCD, the inventors conclude that improving cognitive dysfunction will further contribute to the overall improvement of OCD.

[0667] Improvement in OCD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0668] Improvement in OCD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in OCD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] Patients with body dysmorphic disorder (BDD) mistakenly perceive defects in their appearance, which interfere with their ability to function in daily life due to anxious beliefs, ritualistic behaviors, and psychological distress.

[0670] Patients with BDD can suffer from treatment-resistant forms of the disorder.

[0671] A variety of cognitive deficits have been identified in patients with BDD, including impairments in memory, decision-making, and attentional set-shifting, as well as cognitive interference and inhibition of visuospatial search.

[0672] Cognitive rehabilitation may be useful in addressing the cognitive deficits seen in people with BDD.

[0673] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0674] Functional magnetic resonance imaging (FMRI) of patients suffering from BDD reveals alterations within and / or between specific brain regions located in the default mode network, dorsal attention network, and salience network. These altered functional connectivity suggests that maladaptive self-referential thinking may reflect an inability to regulate the balance between internal and external attention.

[0675] Treating patients suffering from BDD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of the BDD.

[0676] The reduction or elimination of cognitive dysfunction in patients with BDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0677] The reduction or elimination of cognitive dysfunction in patients with BDD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0678] The reduction or elimination of cognitive dysfunction in patients with BDD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0679] The reduction or elimination of cognitive dysfunction in patients with BDD, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0680] The reduction or elimination of cognitive dysfunction in patients with BDD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0681] The reduction or elimination of cognitive dysfunction in patients with BDD, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0683] Improvement in BDD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0684] The improvement in BDD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in BDD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] Post-traumatic stress disorder (PTSD) Post-traumatic stress disorder (PTSD) is a mental health condition that can develop based on a fatal event that a patient has experienced or witnessed. Symptoms can include flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event.

[0686] Patients with PTSD can suffer from treatment-resistant forms of the disorder.

[0687] Post-traumatic stress disorder (PTSD) is characterized by abnormal cognitive and emotional processes that interfere with daily life after a trauma. Abnormalities in the cognitive domains of memory, attention, problem-solving, and planning have been described as hallmarks of PTSD.

[0688] Cognitive theories of PTSD suggest an interplay between emotion and cognition in the development of PTSD symptoms and traits. In particular, it is thought that an overemphasis on threat-seeking cognitive processes may explain why fewer cognitive resources are allocated to non-threat-related information, leading to attentional bias.

[0689] The severity of PTSD symptoms correlates with declines in cognitive performance, particularly with regard to psychomotor speed / attention and memory.

[0690] PTSD can be assessed using the Clinical Diagnostic PTSD Scale for DSM-5 (CAPS-5), a structured diagnostic interview for PTSD that corresponds to DSM-5 criteria for PTSD.

[0691] Cognitive dysfunction in PTSD can be assessed using the Montreal Cognitive Assessment (MoCA).

[0692] Resting-state functional magnetic resonance imaging analysis of patients with PTSD reveals alterations within and / or between regions located in the default mode network and salience network.

[0693] Treating patients suffering from PTSD and associated cognitive dysfunction, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of the PTSD.

[0694] The reduction or elimination of cognitive dysfunction in patients with PTSD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] The reduction or elimination of cognitive dysfunction in patients with PTSD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] The reduction or elimination of cognitive dysfunction in a patient suffering from PTSD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0697] The reduction or elimination of cognitive dysfunction in patients with PTSD, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0698] As mentioned above, cognitive dysfunction is closely related to PTSD.Therefore, improving cognitive dysfunction will also lead to the improvement of PTSD.Because cognitive dysfunction also affects other aspects of PTSD, the inventors conclude that improving cognitive dysfunction will further contribute to the overall improvement of PTSD.

[0699] Improvement in PTSD in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0700] Improvement in PTSD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in PTSD in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0701] pain disorders Cognitive dysfunction occurs in pain sufferers and is associated with chronic pain.

[0702] Chronic pain, also called persistent pain, is long-term pain that persists beyond the normal recovery period, despite medication or treatment, for example, after an injury or surgery. Patients may also suffer from chronic pain without any apparent cause, such as a history of injury or surgery.

[0703] Chronic pain is associated with impaired cognitive function, which may be secondary to increased competition for cognitive resources. Cognitive dysfunction is most evident in the domains of reduced attention, memory, executive function, and processing speed. A bidirectional relationship exists between cognition and pain.

[0704] Cognitive function can be assessed objectively using subjective self-report measures or using formal, empirically validated neurophysiological tests that focus on one or more aspects of cognition.

[0705] A suitable test to assess cognitive dysfunction is the Montreal Cognitive Assessment (MoCA).

[0706] Chronic pain patients exhibit brain changes in brain function and structure. These changes are associated with the persistence of pain long after the initial pain input has disappeared. Many brain regions and networks involved in pain processing are also involved in other sensory tasks, particularly cognitive tasks. Resting-state functional magnetic resonance imaging reveals changes in distinct regions within and / or between the default mode network, the somatomotor / sensorimotor network, and the salience network.

[0707] Treating patients suffering from chronic pain 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 chronic pain.

[0708] The reduction or elimination of cognitive dysfunction in patients suffering from chronic pain is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0709] The reduction or elimination of cognitive dysfunction in patients suffering from chronic pain occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0710] The reduction or elimination of cognitive dysfunction in a patient suffering from chronic pain is reflected by at least an improvement in Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0711] The reduction or elimination of cognitive dysfunction in patients suffering from chronic pain, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] As mentioned above, cognitive dysfunction is closely related to chronic pain. Therefore, improving cognitive dysfunction will also lead to improving chronic pain. Because cognitive dysfunction also affects other aspects of chronic pain, the inventors conclude that improving cognitive dysfunction will further contribute to the overall improvement of chronic pain.

[0713] Improvement in chronic pain in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0714] The improvement in chronic pain in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in chronic pain in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0715] Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain throughout the body or in multiple areas, accompanied by fatigue, sleep disturbances, memory and mood problems. Patients may also experience muscle and joint stiffness, tenderness to touch, numbness or tingling in the arms and legs, problems with concentration, clear thinking and memory (sometimes called "fibromyalgia fog"), increased sensitivity to light, sound, smells and temperature, or digestive problems such as bloating and constipation.

[0716] Research has shown that people with fibromyalgia have increased pain sensitivity, causing them to feel pain when others do not.

[0717] Patients with fibromyalgia often report forgetfulness and cognitive decline, referred to as "fibromyalgia fog." "Fibromyalgia fog" is a subjectively experienced cognitive dysfunction associated with fibromyalgia. It includes loss of mental clarity (mental fog) and impaired attention and memory. The combination of pain, fatigue, poor sleep quality, and cognitive dysfunction often interferes with the ability to function at home and at work.

[0718] Previous treatments for fibromyalgia are symptomatic.

[0719] Cognitive dysfunction in fibromyalgia can be assessed using the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE).

[0720] Brain imaging and other studies have revealed evidence of altered signaling in the neural pathways that transmit and receive pain in people with fibromyalgia. These changes may also contribute to the fatigue, sleep disturbances, and cognitive impairment experienced by many people with the disorder.

[0721] Resting-state functional magnetic resonance imaging in patients with fibromyalgia shows altered functional connectivity within and / or between the DMN and the executive attention network, and between the DMN and the insular cortex (a brain region known to process evoked pain).

[0722] Treating patients suffering from fibromyalgia and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction and leads to improvement of fibromyalgia.

[0723] The reduction or elimination of cognitive dysfunction in a patient suffering from fibromyalgia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0724] The reduction or elimination of cognitive dysfunction in a patient suffering from fibromyalgia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0725] The reduction or elimination of cognitive dysfunction in a patient suffering from fibromyalgia is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0726] The reduction or elimination of cognitive dysfunction in patients with fibromyalgia, as reflected by an improvement in MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0727] The reduction or elimination of cognitive dysfunction in a patient suffering from fibromyalgia is reflected by at least an improvement in Mini-Mental Status Examination (MMSE) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0728] The reduction or elimination of cognitive dysfunction in patients with fibromyalgia, as reflected by an improvement in MMSE score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MMSE score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0729] As mentioned above, cognitive dysfunction is closely related to fibromyalgia. Therefore, improving cognitive dysfunction will also lead to the improvement of fibromyalgia. Because cognitive dysfunction also affects other aspects of fibromyalgia, the present inventors conclude that improving cognitive dysfunction will further contribute to the overall improvement of fibromyalgia.

[0730] Improvement in fibromyalgia in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0731] Improvement in fibromyalgia in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in fibromyalgia in patients also suffering from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0733] In some patients, the headache is preceded or accompanied by symptoms known as auras, which may include visual disturbances such as flashing lights or blind spots, or other disturbances such as tingling on one side of the face or in the arms or legs and difficulty speaking.

[0734] Migraineurs often report cognitive dysfunction, particularly deficits in information processing speed, basic attention, executive function, verbal and non-verbal memory, and language skills.

[0735] Cognitive symptoms are frequently present during the prodromal and headache phases of a migraine attack and may persist in the aftereffects. Some migraine sufferers also report cognitive symptoms outside of the migraine attack.

[0736] Cognitive dysfunction in patients suffering from migraine can be assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA).

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

[0738] Resting-state network analysis shows differences in patients suffering from migraine compared to healthy controls. Studies during a migraine attack reveal significant abnormalities in networks involved in mediating the cognitive, attentional, somatosensory, and affective components of pain.

[0739] Treating patients suffering from migraine 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 migraine headaches.

[0740] The reduction or elimination of cognitive dysfunction in a patient suffering from migraine is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0741] The reduction or elimination of cognitive dysfunction in a patient suffering from migraine occurs within 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 a patient suffering from migraine preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0742] The reduction or elimination of cognitive dysfunction in a patient suffering from migraine is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0743] The reduction or elimination of cognitive dysfunction in patients suffering from migraine, as reflected by an improvement in the MoCA score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in the MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0744] The reduction or elimination of cognitive dysfunction in a patient suffering from migraine is reflected by at least an improvement in Mini-Mental State Examination (MMSE) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0745] The reduction or elimination of cognitive dysfunction in patients suffering from migraine, as reflected by an improvement in MMSE score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MMSE score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0746] As mentioned above, cognitive dysfunction and migraine are closely related. Therefore, improving cognitive dysfunction will also lead to improvement of migraine. Because cognitive dysfunction also affects other aspects of migraine, the inventors conclude that improving cognitive function will further contribute to the overall improvement of migraine.

[0747] Improvement in migraine headaches in patients who also suffer from associated cognitive dysfunction, as reflected by a decrease in CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., 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.

[0748] Improvement in migraine headaches in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in migraine headaches in patients who also suffer from associated cognitive dysfunction, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0749] Mental and behavioral disorders resulting from psychoactive substance use Substance use disorder (SUD) is a mental disorder that affects a person's behavior and causes them to lose control over their use of substances such as legal or illegal drugs, alcohol, or medicines. Symptoms can range from moderate to severe, with addiction being the most severe form of SUD.

[0750] Cognitive abnormalities can be considered a hallmark of substance use disorders, and it is well documented that patients with substance use disorders have attentional biases that contribute to drug-seeking behavior as well as other reward-seeking behaviors.

[0751] Other prominent cognitive domains affected in patients with substance use disorders include working memory, the executive decision-making system, and social metacognition.

[0752] Neurocognitive impairments persist beyond the typical period of intoxication and acute substance or drug withdrawal. Neurocognitive impairments may persist, or improvements in neurocognitive performance may be seen over many months.

[0753] Although nonspecific impairments of various cognitive abilities can occur with almost all substances of abuse and with a variety of drugs, some patterns occur more frequently with selected drug classes. For example, sedatives, hypnotics, or anxiolytics exhibit greater impairment of memory than other cognitive functions. Alcohol-induced cognitive dysfunction often manifests as a combination of impairments in executive function and memory and learning domains.

[0754] Treatment approaches that target attentional bias in some substance use disorders have led to improved outcomes.

[0755] The Screening for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA) can be used to specifically assess cognitive dysfunction.

[0756] Individuals with SUDs are known to exhibit neurological deficits, particularly deficits in cognitive control associated with altered connectivity within and / or between higher-order cognitive networks, such as the default mode network, salience network, and central executive network, as well as the limbic and reward networks.

[0757] Treating patients suffering from SUD and associated cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, resulting in improvement of the SUD.

[0758] The reduction or elimination of cognitive dysfunction in patients with SUD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0759] The reduction or elimination of cognitive dysfunction in patients with SUD occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0760] The reduction or elimination of cognitive dysfunction in a patient suffering from a SUD is reflected by at least an improvement in the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0761] The reduction or elimination of cognitive dysfunction in patients with SUD, as reflected by an improvement in MoCA score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in MoCA score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0762] The reduction or elimination of cognitive dysfunction in a patient with a SUD is reflected by at least an improvement in the Screening for Cognitive Impairment in Psychotic Disorders (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0763] The reduction or elimination of cognitive dysfunction in patients with SUD, as reflected by an improvement in SCIP score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive dysfunction, as reflected by an improvement in SCIP score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0764] As mentioned above, cognitive dysfunction is closely related to SUD. Therefore, improving cognitive dysfunction will also lead to improvement of SUD. Because cognitive dysfunction also affects other aspects of SUD, the inventors conclude that improving cognitive dysfunction will further contribute to the overall impr...

Claims

1. A pharmaceutical composition for treating cognitive impairment in a patient suffering from cognitive impairment, comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT is administered via an intravenous, intramuscular, or subcutaneous route.

2. The pharmaceutical composition according to claim 1, 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.

3. The pharmaceutical composition according to claim 1, wherein the patient suffers from a mental disorder or neurological disorder related to the cognitive impairment.

4. The pharmaceutical composition according to claim 3, wherein the patient suffering from a mental disorder or a neurological disorder is suffering from a treatment-resistant form of the said disorder.

5. The pharmaceutical composition according to claim 1, wherein the patient suffers from a disorder characterized by depressive episodes related to cognitive impairment.

6. The pharmaceutical composition according to claim 5, wherein the patient is currently suffering from a major depressive episode.

7. The pharmaceutical composition according to claim 1, wherein the patient suffers from major depressive disorder (MDD) related to the cognitive impairment.

8. The pharmaceutical composition according to claim 7, wherein the patient suffering from MDD is suffering from a treatment-resistant form of the disorder.

9. The pharmaceutical composition according to claim 1, wherein the cognitive impairment is reduced or eliminated by the treatment described above.

10. The pharmaceutical composition according to claim 1, wherein the reduction or disappearance of the cognitive impairment is observed about two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at least one day after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours after the last dose; at least seven days; at least fourteen days; and / or at least twenty-eight days.

11. The pharmaceutical composition according to claim 3, wherein the treatment leads to improvement of the diagnosed disorder in a patient who also suffers from related cognitive impairment.

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

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

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

15. The pharmaceutical composition according to claim 14, wherein each subsequent dose is administered in a larger amount than the previous dose.

16. The pharmaceutical composition according to claim 14, wherein the patient receives a subsequent dose unless the patient experiences a hallucinogenic peak experience.

17. The pharmaceutical composition according to claim 14, wherein the interval between two administrations is 1 hour or more and 24 hours or less.

18. The pharmaceutical composition according to claim 16, wherein the manifestation of the hallucinatory peak experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (mystical, positive mood, transcendence of time and space, and inexpressibility), or by achieving at least 60% of the maximum possible score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving at least 75 in the Peak Experience Scale (PES) Total Score.

19. The pharmaceutical composition according to claim 15, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous injection.

20. The pharmaceutical composition according to claim 1, wherein the cognitive impairment is measured using the Montreal Cognitive Assessment (MoCA).