Treating cognitive impairment

Abstract

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

Description

[Technical Field]

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

[0002] Additionally, cognitive impairment may also give rise to unspecified neurocognitive impairment, i.e., a disorder that exhibits characteristic symptoms of neurocognitive impairment that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning but does not meet all diagnostic criteria for any etiologically related disorder.

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

[0004] Cognitive impairment 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 impairment is associated with several psychiatric or neurological disorders and also occurs in patients suffering from certain medical conditions that lead to related psychiatric or neurological conditions.

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

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

[0008] Cognitive impairment is associated with a lower quality of life, more severe depression, greater anxiety, higher perceived stress, and a decline in overall psychological well-being.

[0009] Cognitive impairment requires detailed evaluation and management.

[0010] Cognitive impairment 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 impairment associated with a psychiatric or nervous system disorder, known treatments for the psychiatric or nervous system disorder do not always improve the cognitive impairment.

[0013] For example, patients with major depressive disorder (MDD) often complain of impaired concentration, which negatively impacts daily functioning, and these attentional impairments are not alleviated by current first-line treatments. Currently, selective serotonin reuptake inhibitors (SSRIs), the first-line class of pharmacological treatment for depression, have not generally been shown to reduce or even eliminate cognitive impairment. Many studies have been primarily observational or have used combinations of multiple drugs, but have not demonstrated changes in sustained, selective, or divided attention, despite improvements in mood symptoms.

[0014] Similar observations have been made in connection with the treatment of other psychiatric or nervous system disorders.

[0015] Therefore, there is a need for improved methods for the treatment of cognitive impairment. 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 impairment.

[0019] The present invention also relates to 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a cognitive impairment, wherein the cognitive impairment 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, in particular complex attention.

[0020] The present invention further relates to 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use in treating a patient suffering from a cognitive impairment affecting one or more subdomains of the complex attention of the cognitive domain selected from sustained attention, divided attention, selective attention, and processing speed, in particular the sustained attention subdomain of the complex attention of the cognitive domain.

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

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

[0023] Patients may also suffer from sleep disorders associated with cognitive impairment.

[0024] The present invention also provides dosage ranges and regimens useful for treating sleep disorders. DETAILED DESCRIPTION OF THE INVENTION

[0025] 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 an equimolar amount is used.

[0026] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed by a licensed professional in accordance with accepted medical practice with a cognitive impairment, or a human subject who has been diagnosed by a licensed professional in accordance with accepted medical practice with a psychiatric or nervous system disorder associated with cognitive impairment, in which case assessment of cognitive impairment may or may not be part of the diagnosis.

[0027] Diagnosis of psychiatric 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 become clear from the description 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 themselves to believe that they suffer from the disorder in question.

[0028] As used in the context of the present invention, unless otherwise indicated, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and 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.

[0029] "Treatment of cognitive impairment" is intended to include the management and care of a patient for the purpose of addressing cognitive impairment, and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of cognitive impairment or to eliminate cognitive impairment.

[0030] The cognitive impairment may be associated with a sleep disorder, e.g., insomnia, a psychiatric or nervous system disorder, or another medical condition. The cognitive impairment may take the form of a neurocognitive impairment.

[0031] The patient may suffer from 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. At least two previous treatment courses are particularly those carried out during the current episode of the disease, for example, when the patient suffers from a disorder characterized by depressive episodes, they are carried out during the current episode of depression.

[0032] 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.

[0033] "Clinical response" includes, but is not limited to, improvements on rating scales assessing (i) cognitive impairment or aspects of cognitive impairment, and / or (ii) psychiatric or nervous system disorder or aspects of such disorder, and / or (iii) medical conditions leading to related mental or nervous system conditions, and / or (iv) sleep.

[0034] The severity of the condition and changes in severity can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, therapeutic response, and treatment effectiveness.

[0035] 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).

[0036] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of mental illness in this patient?" This is rated on a 7-point scale: 1 = normal (no illness at all), 2 = borderline mental illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = patient with very severe illness.

[0037] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0038] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, the clinician compares the patient's overall clinical condition with 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 little; 4 = no change from baseline (before treatment began); 5 = very little; 6 = very little; 7 = very little since treatment began."

[0039] 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).

[0040] In addition to the individual items of the scales as described herein, subcombinations of the individual items may also be used to assess specific disease aspects.

[0041] 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. Preferably, the active compound is administered by nasal inhalation, by buccal administration, or by sublingual administration.

[0042] As used in the context of this 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.

[0043] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and extremely small suspended solids and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When a percentage of "degradation products" is described in the context of the present invention, it refers to the amount of 5-MeO-DMT degradation products present in the sample divided by the amount of 5-MeO-DMT present in the sample plus the amount of 5-MeO-DMT degradation products present in the sample, multiplied by 100%, i.e., (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample) / ((the amount of 5-MeO-DMT present in the sample) + (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample)) × 100%. As used herein, the term "impurities" refers to undesirable compounds that contaminate a 5-MeO-DMT (or a pharmaceutically acceptable salt thereof) sample. The impurities may be contained in the starting material prior to aerosol formation, or the impurities may be decomposition products.

[0044] The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) / (the amount of 5-MeO-DMT present + the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0045] The term "mass median aerodynamic diameter" (MMAD) refers to the calculated diameter where 50% of the particles present in the aerosol are larger and 50% are smaller. The term "aerosol particle mass concentration" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle generation rate" refers to the mass of aerosolized 5-MeO-DMT per unit time of aerosolization.

[0046] Cognitive impairment Cognition includes the skills required for thinking, remembering, paying attention and solving problems.When these skills are lost or reduced, cognitive dysfunction occurs, and this term used herein refers to the defect or disorder of any domain of cognition.Cognitive dysfunction can be one of the symptoms of the underlying pathology of patients.

[0047] DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0048] Cognitive impairment can affect one or more of these domains, and indeed, cognitive abilities are highly interrelated, and it is not uncommon for more than one domain to be affected.

[0049] For example, the domain complex attention has the subdomains sustained attention (also commonly called "concentration" or "focus"), divided attention, selective attention, and processing speed.

[0050] Complex attention therefore clearly encompasses aspects important for executive function and various cognitive tasks such as learning and memory. Cognitive control or executive function is essentially about directing attention, and perception and decision-making are significantly influenced by attentional abilities.

[0051] As a result, attention is not only tested in isolation, but also, for example, by cognitive control tasks / executive functions. If attention is impaired, other types of cognitive abilities are likely to be impaired as well. Before one can understand language, recognize visual-spatial relationships, remember information, or solve a problem, one must attend to a stimulus.

[0052] The term cognitive impairment, as used herein, refers to an acquired condition and thus represents a decline from a previously achieved level of functioning, and may relate to a variety of processes.

[0053] 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 underlying age-related deficits in processing speed, attention, memory, and executive function, which constitutes cognitive aging.

[0054] Apart from normal aging, cognitive impairment may be associated with psychiatric or nervous system disorders, or some other medical conditions.

[0055] Psychiatric or nervous system disorders leading to or associated with cognitive impairment include disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder); anxiety disorders, such as separation anxiety disorder, cyclophobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, Examples include chronic pain, fibromyalgia, and migraine; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic 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 post-COVID pathology. Cognitive dysfunction can also occur in patients with sleep disorders, such as insomnia.

[0056] Additionally, cognitive impairment can also result in disorders that exhibit characteristic symptoms of neurocognitive dysfunction that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet all diagnostic criteria for any etiologically related disorder.

[0057] Cognitive impairment can take the form of neurocognitive dysfunction.

[0058] Mild neurocognitive impairment, also known as mild cognitive impairment, is characterized by a moderate cognitive decline from a previous level of ability in one or more cognitive domains. Affected individuals are still able to maintain their independence and perform daily tasks. However, they typically function at a suboptimal level. Compensatory strategies to maintain independence make daily tasks more challenging.

[0059] Severe neurocognitive impairment is characterized by a significant cognitive decline from a previous level of ability in one or more cognitive domains. The cognitive impairment interferes with independence in daily living.

[0060] Measurement of cognitive impairment Cognitive impairment can be assessed by questionnaire or by neuropsychological assessment.

[0061] The questionnaire assesses the mental state of the patient based on observations made by the patient, caregiver, or clinician who administers the questionnaire. Questionnaires used to assess whether a patient suffers from a specific psychiatric or nervous system disorder may include items related to cognitive function.

[0062] Neuropsychological evaluation is the process of comprehensively assessing a person's cognitive, psychological / emotional, and behavioral functioning. A central part of a neuropsychological evaluation is the administration of neuropsychological tests for the formal assessment of cognitive function.

[0063] Performance on these tests is compared to norms appropriate for the patient's age, educational achievement, and cultural background. Tests often use a series of ability-based questions, also known as neuropsychological test batteries.

[0064] 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.

[0065] Common tests used to assess cognitive impairment include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screen for Cognitive Impairment in Psychiatry (SCIP), and the Matrix Consensus Cognitive Battery (MCCB).

[0066] The Montreal Cognitive Assessment (MoCA) is a widely used screening test to detect cognitive impairment. It assesses different cognitive domains: short-term memory, visuospatial ability, executive function, attention, concentration and working memory, language, and orientation to time and space. There is a total possible score of 30, with a score of 26 or higher considered normal, a score of 18-25 considered mild cognitive impairment, a score of 10-17 considered moderate cognitive impairment, and a score below 10 considered severe cognitive impairment.

[0067] The Mini-Mental State Examination (MMSE) is an 11-question measure that tests five domains of cognitive function: orientation, notation, attention and calculation, recall, and language. The maximum score is 30. Raw scores may need to be adjusted for educational achievement and age.

[0068] Herein, four cutoff 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.

[0069] Repeated use of the MMSE is suitable for measuring changes in cognitive status.

[0070] The Mini-Cog™ is a short cognitive impairment screening questionnaire. It includes a clock drawing test along with a three-word recall test. The clock drawing test assesses many cognitive domains that may be affected, including executive function, visuospatial ability, motor programming, and attention. For each of the three words correctly recalled after administering the clock drawing test, one point is awarded, and a correctly drawn clock is worth two points. A score below four indicates cognitive impairment.

[0071] The Screen for Cognitive Impairment in Psychiatry (SCIP) is a well-established screening scale for the assessment of cognitive abilities in psychiatric patients.

[0072] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Verbal Learning Test-Delta (VLT-D), and Processing Speed ​​Test (PST). There are three different test formats to facilitate repetition of the test 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 below 70 indicates cognitive impairment.

[0073] Cognitive impairment can also be assessed by the Matrices Consensus Cognitive Battery (MCCB) or by one or more of its various subtests: the Trail Making Test, Part A (processing speed test); the Brief Cognitive Assessment Scale for Schizophrenia, Symbol Code Sorting subtest (processing speed); the Hopkins Verbal Learning Test-Revised, immediate recall, three learning trials only (verbal learning); the Wechsler Memory Scale, 3rd ed., Spatial Span subtest (working memory (nonverbal)); the Letter-Number Span test (working memory (verbal)); the Neuropsychological Assessment Battery, Maze subtest (reasoning and problem solving); the Brief Visuospatial Memory Test-Revised (visual learning); the Category Fluency Test, Animal Name (processing speed); the Mayer-Salovey-Caruso Emotional Intelligence Test, Emotion Branch Management (social cognition); and the Continuous Performance Test, Identical Pairs version (attention / alertness).

[0074] Test batteries are suitable for measuring cognitive change.

[0075] 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).

[0076] Scales for assessing psychiatric and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders, and these are based on self-report or clinician-administered tests.

[0077] 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, as described in more detail below.

[0078] Treatment outcome is assessed using one or more indexes or scales at one or more time points after the course of treatment has ended.

[0079] The assessment can be performed after the acute hallucinatory experience has subsided. A suitable time point for early assessment is generally about 2-3 hours after the last dose. Early assessments can generally be performed, for example, about 2 hours or about 3 hours after the last dose.

[0080] However, assessment of the effect on sleep disturbances may be performed as early as the day after treatment (ie, Day 1) so that treated patients have had the opportunity to get at least one night's sleep.

[0081] 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 case, no later than overnight after the last dose to no later than 36 hours after the last dose. Evaluation can occur after about 24 hours.

[0082] Assessment on day 7 or assessment at day 7 refers to the assessment on the seventh day after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0083] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response at an early time point (for example, 2 hours) after drug administration, based on the endpoint that is established with a longer recall time (for example, MADRS is usually 7 days), such endpoint can be reasonably modified (for example, the recall time of MADRS is changed to 2 hours, and the sleep item recorded at the baseline before drug administration is carried forward).The same applies to any other scales used herein, unless recall time is clearly indicated.

[0084] 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.

[0085] 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 times adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0086] Mechanisms underlying cognitive impairment Brain processes can be studied by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0087] Functional brain images are obtained within minutes. Patterns of low-frequency BOLD signal oscillations are observed throughout the brain. Decomposition of this spontaneous signal reveals discrete regions with correlated and anticorrelated fluctuations.

[0088] In this way, resting-state fMRI can be used to characterize large-scale functional networks, also called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any 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).

[0089] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in fMRI experimental tasks.

[0090] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, and resting-state networks have been characterized with respect to aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0091] RSNs have been shown to contribute to 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, associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more other resting-state networks.

[0092] Resting-state fMRI is particularly advantageous when testing 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.

[0093] Cognitive processes are reflected by the functional connectivity of specific brain regions within and / or between regions located in different networks.

[0094] In particular, certain core networks, also called "higher-order cognitive networks," appear to be crucial for most mental activities.

[0095] The frontoparietal control network (FPCN), also known as the frontoparietal control 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.

[0096] Another core network is the default mode network (DMN). The DMN contains brain regions that are most active when a person's attention is not focused on any specific task. DMN activity is associated with self-monitoring, episodic memory, memory consolidation, social and self-referential cognition, integration of cognitive and emotional processing, and the free-thinking of non-task-related daydreams.

[0097] The third network is the salience network, also known as the cingulo-opercular network. This network is involved in identifying salient stimuli and events—that is, what other brain networks need to pay attention to. This network plays a central role in governing mental processes and behavior.

[0098] The fourth network is the dorsal attention network (DAN), which is associated with global goal-directed attention processes.

[0099] Each of the above networks does not operate in isolation. In fact, there are numerous connections between them. Cooperation between networks is crucial for task-specific functions.

[0100] Across the lifespan, brain networks undergo functional reorganization with concurrent implications for cognition. During healthy aging, age-related changes are observed in higher-order cognitive networks.

[0101] Patients suffering from cognitive impairment exhibit altered functional connectivity 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.

[0102] In many instances, resting-state networks involved in cognition are involved in disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder); anxiety disorders, such as separation anxiety disorder, cyclophobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, and phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); somatoform disorders, such as body dysmorphic disorder (BDD); obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, and fibromyalgia. and migraine; mental and behavioral disorders resulting from the use of psychoactive substances, e.g., substance use disorder (SUD); psychotic disorders, e.g., schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, e.g., Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia; Parkinson's disease (PD); Huntington's disease (HD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, e.g., schizotypal personality disorder and borderline personality disorder; chronic fatigue syndrome; affected by a psychiatric or nervous system disorder, such as a psychiatric or nervous system disorder associated with HIV, traumatic brain injury, or post-COVID pathology.

[0103] Resting-state networks involved in cognition are also affected by mental or nervous system conditions that are the result of certain medical conditions, as well as unspecified neurocognitive dysfunction.

[0104] Furthermore, resting-state networks involved in cognition are affected by sleep disorders, such as insomnia, and indeed cognitive impairment and sleep disorders are correlated.

[0105] Patients with sleep disorders have poorer cognitive function, and patients with cognitive impairment often also suffer from sleep disorders.

[0106] Active Agent The above discussion indicates that cognitive impairment is characterized by several aspects and, as such, poses a significant disease burden and is amenable to appropriate treatment.

[0107] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of cognitive dysfunction and improve the condition overall.

[0108] 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.

[0109] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] The inventors have considered that in order to avoid inducing mania or hypomania, or at least to reduce the risk of inducing mania or hypomania, the compound administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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).

[0122] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0123] 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.

[0124] 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 inhalation, 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.

[0125] 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. 3Estimate nonspecific binding using [H]LSD and serotonin, and K i was determined to be 2.3 nM.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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 can lead to disease states, particularly those involving sleep disorders. In patients with sleep disorders, resting-state functional connectivity analysis reveals altered functional connectivity between the SNU and regions within the default mode network.

[0130] 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.

[0131] 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" the functional connectivity of networks and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders and / or cognitive impairment.

[0132] 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 impairment, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0133] Another characteristic of 5-MeO-DMT is its short half-life.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] The properties of 5-MeO-DMT make the compound particularly suitable for treating cognitive dysfunction, particularly in patients suffering from a psychiatric or nervous system disorder, or a medical condition leading to a related psychiatric or nervous system condition; in patients suffering from a sleep disorder, e.g., insomnia; and in patients suffering from an unspecified neurocognitive dysfunction.

[0138] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0139] 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.

[0140] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0141] 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.

[0142] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0143] 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.

[0144] 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.

[0145] Methods for preparing these compounds are known in the art.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0150] 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.

[0151] 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.

[0152] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0153] 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).

[0154] Methods for preparing the prodrugs described herein are known in the art.

[0155] 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.

[0156] 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.

[0157] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration, or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred administration route is inhalation. Preferably, a therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0158] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0159] Buccal or sublingual administration can also be by a pharmaceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in formulations commonly known in the art (e.g., tablets, films, sprays, creams).

[0160] Administration is typically via inhalation of an aerosol. Such an aerosol contains (a) a pharmaceutically acceptable gas and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / L to about 18 mg / L (e.g., about 0.5 mg / L to about 12.5 mg / L, preferably about 1.3 mg / L to about 10 mg / L, particularly about 2 mg / L to about 9 mg / L). The pharmaceutically acceptable gas is preferably air.

[0161] The aerosol particles preferably contain less than 1 wt. % impurities, particularly less than 0.5 wt. % impurities, and more preferably less than 0.5 wt. % 5-MeO-DMT decomposition products, particularly less than 0.2 wt. % 5-MeO-DMT decomposition products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0162] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0163] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0164] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0165] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to generate aerosol particles. The thickness of the thin layer can be less than about 10 μm, particularly less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

[0166] A thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via air passing over the layer, or alternatively, a thin layer of 5-MeO-DMT formed on a solid support can be exposed to thermal energy via the solid support.

[0167] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a flow rate of about 12 l / min for about 15 seconds.

[0168] The aerosol particles can be contained in a volume of about 3 liters or less, particularly a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0169] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. Such an aerosol has a suitable aerosol particle mass concentration so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0170] The aerosol useful in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is very difficult to predict the conditions suitable for safe, efficient and predictable aerosolization, especially when the aerosol is to be used to systemically deliver the compound to a patient via the lungs. Relevant variables in this context include: a) the dose of the compound; b) the morphological state of the compound that is made aerosolizable (e.g., crystalline form or thin layer form); c) the amount of thermal energy that the compound is exposed to (defined by temperature and exposure duration); and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0171] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products; "efficient" means that the dose is aerosolized to a defined extent, preferably nearly completely or completely, that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., within a single deep breath); and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0172] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) briefly exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature, and c) providing a controlled amount of air so that an aerosol is formed.

[0173] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) can be delivered to a patient by a single inhalation.

[0174] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, which contain less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT degradation product drug by aerosol volume and can be delivered to a patient by a single inhalation, is achieved by specifying a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by the air flow rate and duration of the air flow).

[0175] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, whereby the air is heated. The temperature of the heated air passing over the thin layer can range from about 180°C to about 260°C. The temperature of the air passing over the thin layer can be, in particular, about 210°C.

[0176] Alternatively, the thin layer of 5-MeO-DMT can be exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180°C to about 420°C.

[0177] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is highly pure, being at least 99%, preferably at least 99.5% pure.

[0178] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific effective amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Specific preferred amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0179] The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, a cylinder less than 1.0 mm in diameter, a box less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a high surface area to volume ratio (e.g., greater than 100 per meter) and a high surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0180] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (approximately 400 per meter).

[0181] Several different materials are used to construct solid supports. Such material types include, but are not limited to, metals, inorganic materials, carbon-containing materials, and polymers. Examples of material types are: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene, and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0182] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica-, alumina-, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m), and PEG-1000 (Sigma, St. Louis, Mo.). 2 Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0183] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, particularly less than about 7.5 μm, and the thickness of the thin layer can range from about 0.1 μm to about 10 μm, particularly from 0.3 μm to 7.5 μm.

[0184] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of between about 6 liters per minute and about 40 liters per minute, preferably between about 8 liters per minute and about 16 liters per minute, and the duration of the airflow is selected so that the total aerosol volume does not exceed about 3 liters, which is preferably between about 1 liter and 3 liters (e.g., between 2 liters and 3 liters). For example, at an airflow rate of about 6 liters per minute, the duration of the airflow should be less than about 30 seconds. A specific effective airflow rate and duration is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective airflow rate and duration is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective airflow rate and duration is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0185] The aerosol generation rate is greater than 0.1 mg / sec.

[0186] The aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l).

[0187] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, and most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0188] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT degradation products, preferably less than 0.2% wt of 5-MeO-DMT degradation products.

[0189] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT, organized on a solid support as a thin layer less than 5 microns thick, to a temperature of 210°C for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt of 5-MeO-DMT degradation products; and 3) is capable of being delivered to a patient by a single inhalation.

[0190] Those skilled in the art, knowing the aerosol characteristics and aerosolization conditions defined in the present invention, can identify a suitable vaporization device or system that can achieve the required aerosol characteristics. Examples of such suitable vaporization devices or systems include the Volcano Medic Vaporization System (Storz & Bickel, Germany, for example, as disclosed in EP 0 933 093 B1 and EP 1 884 254 B1 and registered Community design 003387299-0001), which includes a dosage capsule with a related drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA, for example, as disclosed in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The generated aerosol is collected in a balloon, from which it can be inhaled by the patient.

[0191] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (administration schemes).

[0192] 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 aspects as defined above.

[0193] Thus, achieving a peak experience more rapidly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0194] 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.

[0195] 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.

[0196] Patients suffering from cognitive impairment, as defined herein, are treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0197] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for cognitive impairment).

[0198] The dosage of 5-MeO-DMT administered to a patient suffering from cognitive impairment, as defined herein, ranges from about 1 mg to about 25 mg, or any amount within this range, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Specific amounts that are effective include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT (e.g., the hydrobromide salt). It should be noted that when a range such as "about 1 mg to about 25 mg" is provided herein, the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0199] In a preferred embodiment, the improved method for treating a patient suffering from cognitive impairment, as defined herein, with a therapeutically effective amount of 5-MeO-DMT comprises producing a clinical response within about 2 hours of administering the 5-MeO-DMT.

[0200] In a preferred embodiment, an improved method for treating a patient suffering from cognitive impairment, as defined herein, with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, including a clinical response occurring within about 2 hours of administering 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.

[0201] In a preferred embodiment, the improved method for treating a patient suffering from cognitive impairment, as defined herein, with a therapeutically effective amount of 5-MeO-DMT comprises administering more than one dose of 5-MeO-DMT.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and treatment block is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific effective amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0206] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0207] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0208] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg, to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increase is 6 mg, the dosage of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage of the third administration will be 18 mg.

[0209] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration and to a dosage selected from about 14 mg to about 20 mg for the third administration, unless the patient has yet to experience a hallucinogenic 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 6 mg, about 12 mg, and about 18 mg.

[0210] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased with each subsequent administration within the first treatment block until it reaches 20 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic 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 a dose of 18 mg, and therefore the highest dosage in the first treatment block was 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0211] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dosage selected from about 14 mg to about 20 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic 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 6 mg, about 12 mg, and about 18 mg.

[0212] It will be understood that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0213] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0214] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum 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).

[0215] The occurrence of a "psychedelic peak experience" in a patient can also be identified by achieving at least 60% of the maximum 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).

[0216] 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 did it make you feel? 3. How profound (i.e., meaningful) was the experience?

[0217] Treatment of cognitive impairment According to the present invention, cognitive impairments occurring in patients suffering from psychiatric or nervous system disorders, or medical conditions leading to related psychiatric or nervous system conditions, can be treated. Additionally, cognitive impairments occurring in patients suffering from sleep disorders, such as insomnia, can also be treated.

[0218] Cognitive impairment in neurocognitive impairment not otherwise specified is similarly treatable.

[0219] In patients suffering from cognitive impairment associated with another medical condition, such as those mentioned above, treatment of the cognitive impairment according to the present invention will lead to an improvement in the medical condition associated with the cognitive impairment.

[0220] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0221] 5-MeO-DMT administered to patients disrupts established patterns of functional connectivity within and / or between resting networks. This disruption resets the pathologically unhealthy connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0222] Thus, in accordance with the present invention, by affecting these networks with the therapies described herein, cognitive impairment 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 health condition that leads to an associated psychiatric or nervous system condition, the associated psychiatric or nervous system condition is also improved; if the treated patient suffers from a sleep disorder, e.g., insomnia, the sleep disorder, e.g., insomnia, is also improved; and if the treated patient suffers from an unspecified neurocognitive dysfunction, one or more other symptoms of the disorder are also improved.

[0223] To further support the clinical application of 5-MeO-DMT in patients suffering from cognitive impairment, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting specific improvements in cognitive impairment that are also commonly seen in patients with other disorders.

[0224] 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 impairment, as described in more detail below.

[0225] 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 hallucinogenic experience.

[0226] 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 the study was on demonstrating the effectiveness of treatment through improvement in the overall MADRS score, the inventors focused on items across various rating scales and found that certain subscore items similar to those related to cognitive dysfunction are associated with other conditions in which cognitive dysfunction is based on similar altered functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0227] Multiple patients within the pooled cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0228] Furthermore, a particular aspect that can be treated by administration of 5-MeO-DMT is cognitive impairment, particularly difficulty concentrating. 5-MeO-DMT can be administered to a patient to reduce or eliminate cognitive impairment, particularly difficulty concentrating, in the patient.

[0229] The MADRS item that is particularly relevant to concentration and memory problems is "Difficulty concentrating." This item describes difficulty gathering thoughts that gradually deteriorates to the point of being unable to concentrate and function normally, and is scored on a scale ranging from 0 to 6. If the patient has no difficulty concentrating, the score is 0. If the patient only occasionally has difficulty gathering thoughts, the score is 2. If the patient has difficulty concentrating or sustaining thoughts, resulting in a decrease in the ability to read or carry on a conversation, a score of 4 is assigned. If the patient is unable to read or converse, the score is 6.

[0230] The combined MADRS "Difficulty concentrating" score across all eight patients in the study group receiving the individualized dosing regimen was 30 at baseline.

[0231] 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.

[0232] The baseline score for the MADRS item "Difficulty concentrating" across all four patients in the 12 mg group was 16.

[0233] 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.

[0234] Thus, according to the present invention, treating a patient suffering from cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment.

[0235] More particularly, according to the present invention, when a patient suffers from a cognitive dysfunction that 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, treating the patient with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction. For example, when the treatment affects one or more subdomains of complex attention in the cognitive domain selected from sustained attention, divided attention, selective attention, and processing speed, particularly complex attention in the cognitive domain such as sustained attention, the cognitive dysfunction is reduced or eliminated.

[0236] Treatment of cognitive dysfunction and sleep disorders Sleep disorders refer to conditions that are idiopathic or occur in association with a medical condition, such as a psychiatric or nervous system disorder, or a medical condition that leads to a related mental or nervous system condition, and affect the quality, timing or duration of sleep.Sleep disorders affect a person's ability to function properly while awake, and in particular impair cognitive function.

[0237] 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 long period of time, especially within the first cycle of sleep. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle being devoted to REM sleep.

[0238] Normal, healthy sleep consists of different phases, as outlined above, which proceed sequentially and in a tightly regulated sequence throughout the night.

[0239] When this tight regulation is disrupted, sleep disorders occur.

[0240] Common forms of sleep disorders include disorders of sleep initiation and maintenance (insomnia), disorders of excessive somnolence (hypersomnia), disorders of the sleep-wake cycle (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disordered breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0241] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep, waking during the night and having trouble getting back to sleep, waking too early in the morning, groggy sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood problems, difficulty concentrating, or accidents at work or while driving.

[0242] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep intoxication is also a symptom seen in patients with hypersomnia. This is the difficulty in transitioning from sleep to wakefulness. Individuals experiencing sleep intoxication report confused awakenings, disorientation, sluggishness, and repeated returns to sleep.

[0243] Circadian rhythm disorders are characterized by chronic or recurrent sleep disorders resulting from alterations in an individual's internal circadian rhythm or from misregulation between circadian rhythms and desired or required work or social schedules. This dyssynchronization can be temporary or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, the ability to remain awake during desired periods of wakefulness is impaired, and temporary opportunities to return to a normal sleep schedule are unsuccessful.

[0244] Parasomnia refers 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 wakefulness between sleep and wakefulness. Many variations exist in terms of characteristics, severity, and frequency. Parasomnia can impair sleep quality.

[0245] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that depends 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. This occurs when the brain stops sending signals that control breathing, for example, based on an underlying health condition. Central sleep apnea potentially has a significant impact on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation due to microarousals or wakefulness. This can result in excessive daytime sleepiness.

[0246] In recurrent, relatively simple, and usually stereotyped sleep-related movement disorders, movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0247] Lack of adequate sleep quantity and quality can lead to personality changes and may exacerbate existing mental illnesses or even precipitate the onset of new ones. Sleep disorders can also interfere with cognitive function and result in memory impairment. Sleep-deprived subjects may experience difficulty with decision-making, irritability, impaired performance, and slowed reaction times. A recent 2019 systematic review and meta-analysis of studies investigating the relationship between insomnia and cognitive impairment found significant associations with impairments in memory, complex attention, alertness, and executive function. Insomnia can also negatively impact lives by contributing to the development of obesity, diabetes, and heart disease.

[0248] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered primary treatments. If unsuccessful, treatment may also require medication or psychotherapy.

[0249] Available treatments are not successful in all patients, may be associated with side effects, and / or may require prolonged treatment to achieve adequate therapeutic effect.

[0250] In patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not always improve the sleep disorder.

[0251] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treatments for depression do not necessarily improve associated sleep disorders. Most antidepressants have been shown to affect sleep architecture, and while some classes of antidepressants improve sleep, others may cause sleep disorders.

[0252] To assess sleep, parameters such as sleep time, sleep architecture, time to fall asleep, and frequency and duration of nocturnal wakefulness can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and assessment of time to fall asleep, or by self-report measures (questionnaires).

[0253] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic, where various functions are measured during the night, including eye movement, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movement, snoring, and heart rate.

[0254] Another quantitative measurement is actigraphy. Actimetry sensors are worn to measure motor activity, which is continuously recorded and used to assess sleep-wake cycles. This technique allows patients to continue their normal routine while recording the necessary data in a natural sleep environment.

[0255] Sleep onset time can be measured by the Multiple Sleep Onset Time Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep during multiple test naps. An average sleep onset time of approximately 10 minutes is considered normal, with less than 8 minutes indicating a sleep disorder / excessive daytime sleepiness. Correlated analysis of brain activity can aid in further diagnosis of sleep disorders.

[0256] Sleep assessment questionnaires obtain assessment of sleep quality components such as perceived depth of sleep, difficulty waking, and restfulness after sleep, as well as other factors that may affect sleep quality, such as comorbidities and medication use. Because cognitive impairment and sleep disorders are related, cognitive impairment is often part of the assessment.

[0257] Assessment of qualitative aspects of the sleep experience is important because sleep disorders often persist despite normal quantitative measures of sleep.

[0258] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but are also potentially useful for tracking patient progress. Therefore, patient-completed self-report sleep questionnaires are an important mainstay of the assessment of sleep disorders in clinical practice.

[0259] Various sleep quality indices are known. The following indices include examples of questionnaires that assess sleep generally, and questionnaires that assess insomnia, hypersomnia, circadian rhythm disorders, and parasomnias in particular. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0260] Some questionnaires rely on the recall time (recall period) of several days or weeks. This may be suitable for diagnosing sleep disorders, but it is not always suitable for evaluating therapeutic effect, especially the rapid onset of effect after treatment. For some questionnaires, the recall time can be modified so that the score obtained reflects a certain period after treatment. The questionnaires specifically discussed herein for evaluating the effect of treatment on the sleep of patients suffering from certain pathologies rely on the recall time starting from the time when the acute hallucinatory experience after the last administration has subsided. To meet this criterion, the recall time that is usually applied is modified as necessary.

[0261] Generally, sleep quality can be assessed using, for example, the Sleep Quality Score (SQS) and the Sleep-50 questionnaire.

[0262] The Sleep Quality Score (SQS) is a comprehensive assessment tool designed to provide 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, or 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 forget things easily," item 22, "Lack of sleep makes it hard to concentrate at work"), recovery after sleep, sleep initiation and maintenance problems, awakening difficulties, and sleep satisfaction are scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more acute sleep problems (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). Respondents are asked to report their experiences over the past month or another appropriate recall period.

[0263] Successful treatment is indicated by a decrease in score.

[0264] The SLEEP-50 questionnaire consists of 50 items designed to screen for various types of sleep disorders in the general population. This scale consists of nine subscales reflecting some of the most common sleep-related disorders and disorders and factors required for diagnosis, including sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep disorders on daily functioning. For each item, respondents are given a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate how well their experiences over the past month or another appropriate recall period matched that answer.

[0265] To diagnose a sleep disorder, not only must certain subscales (e.g., insomnia) exceed certain cutoff points, but respondents must also meet cutoffs of at least 3 or 4 ("quite a bit" or "very much," respectively) for 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).

[0266] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0267] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other assessment scales include the Insomnia Severity Index, the Espie Sleep Disorders Index, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0268] The Pittsburgh Sleep Quality Index (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.

[0269] 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.

[0270] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. A detailed scoring description for the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0271] 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.

[0272] 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.

[0273] The Insomnia Severity Inventory (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning (item 3, "The extent to which you believe your sleep disturbance interferes with daily functioning (e.g., daytime fatigue, ability to function at work / daily chores, concentration, memory, mood, etc.)"), how significant the respondent perceives their insomnia compared to others, and the overall level of distress caused by the sleep disturbance. Individual responses are scored from 0 (none) to 4 (very), with higher total scores corresponding to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 indicates "subthreshold insomnia," 15–21 indicates "clinical insomnia (moderate severity)," and 22–28 indicates "clinical insomnia (severe)" (A. Shahid et al., loc.cit.). The typical recall period for an ISI is two weeks, although other suitable recall periods may be used herein.

[0274] Successful treatment is indicated by (i) a reduction in score, for example >7 points, particularly >8 points, and preferably (ii) a reduction in score below the cut-off value for clinically significant insomnia.

[0275] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. It involves assessments of restlessness / agitation, mental hyperactivity, consequences of insomnia, and poor sleep readiness. The SDQ specifically addresses beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate how well a particular response about insomnia describes their experience. 1 means "not at all true," while 5 means "very true." Higher scores indicate stronger dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc.cit.).

[0276] Successful treatment is indicated by a decrease in score.

[0277] The Patient-Reported Outcomes Information System (PROMIS®) Sleep Disorders Scale is a universal scale for assessing sleep disorders. The scale is available as a long form and four different short forms (e.g., 4-, 6-, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulty with getting and maintaining sleep over a 7-day period.

[0278] Each item in this 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.

[0279] Successful treatment is indicated by a decrease in T-score.

[0280] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0281] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stopped in traffic. Using a scale of 0 to 3 (0 meaning "never fall asleep" and 3 meaning "likely to fall asleep"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., loc.cit.).

[0282] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0283] The Stanford Sleepiness Scale is a subjective measure of sleepiness, assessing sleepiness at a specific moment in time. Consisting of only one item, the scale requires respondents to select one of seven responses that best describes their current level of perceived sleepiness. A scale ranging from 1 (= feeling active and energetic; alert; wide awake) to 7 (= almost daydreaming; falling asleep easily; losing the effort to stay awake) is used to assess the level of sleepiness (A. Shahid et al., loc.cit.).

[0284] Successful treatment is indicated by a decrease in score.

[0285] Parasomnias can be assessed by the Paris Awakening Disorders Severity Scale (PADSS).

[0286] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnia behaviors, assesses their frequency, and includes an assessment of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0287] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0288] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc.cit.). Appropriate recall times can also be selected.

[0289] Successful treatment is indicated by a decrease in score.

[0290] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire asks respondents to indicate how severely affected they have been by the disorder during the past week using a Likert-type rating. Questions can be divided into two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep problems, impairment of daily functioning, and resulting mood changes). Each of the 10 questions asks respondents to rate their experience with RLS on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores can range from 0 to 40. As a brief scale with good psychometric quality, the rating scale may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes. (A. Shahid et al., loc.cit.)

[0291] Treatment response can be assessed by a decrease in score.

[0292] 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 respective 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 a treatment-induced improvement in the sleep disorder.

[0293] Cognitive dysfunction in insomnia is assessed as part of a sleep assessment questionnaire, such as the SQS or ISI, as described above.

[0294] Common tests available to assess cognitive impairment include the Montreal Cognitive Assessment (MoCA) and the Matrices Consensus Cognitive Battery (MCCB).

[0295] Resting-state fMRI has been widely applied to patients with sleep disorders to better understand the pathophysiology and potential compensatory mechanisms at play.

[0296] Altered resting-state networks may be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0297] In patients with insomnia, dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain important regions that integrate emotional and physical states, and that dysfunctional connectivity within and / or between these networks and other brain regions may underlie alertness, subjective distress, and patients' ongoing sleep deprivation.

[0298] For example, sleep deprivation in healthy subjects leads to changes in functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these changes in brain functional connectivity bear some resemblance to vulnerability patterns in Alzheimer's disease patients.

[0299] The default mode network is affected in patients with hypersomnia: for example, in idiopathic hypersomnia, different DMN hubs, namely the precuneus and medial prefrontal cortex, show significant alterations, and DMN functional connectivity correlates with self-reported sleepiness severity.

[0300] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disorders are associated with functional changes in the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as responsiveness 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 brain functional connectivity at rest have been reported in various diseases associated with circadian rhythm disorders.

[0301] Although functional brain imaging is technically difficult to perform during a parasomnia event, differences in the precuneus have previously been observed in disturbances of arousal that represent non-REM parasomnias.

[0302] The precuneus is involved in analyzing and integrating visual, auditory, and somatic information, as well as monitoring movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnia, the default mode network is affected.

[0303] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, have shown significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in arousal and the sensorimotor system. Sleep-related movement disorders, such as periodic limb movements (PLMs), are reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Cerebellar and thalamic activity may also be observed, along with additional activation of the red nucleus and brainstem.

[0304] In many instances, the resting state networks involved in sleep regulation are also involved in cognition, and therefore, in accordance with the present invention, affecting those networks with therapies according to the present invention will improve sleep disorders and, if the treated patient suffers from cognitive impairment, will also improve that impairment.

[0305] 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.

[0306] The TRD study, described in more detail in the Exemplary section below, assessed, among other things, the MADRS item "Sleep Decreased," which reflects insomnia.

[0307] The "reduced sleep" item on the MADRS reflects 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.

[0308] Aggregate scores for the MADRS item "Decreased Sleep" 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.

[0309] The combined MADRS "Decreased Sleep" 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.

[0310] 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.

[0311] Treating patients suffering from sleep disorders, particularly insomnia, and associated cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and leads to improvement of the sleep disorder, particularly insomnia.

[0312] The reduction or elimination of cognitive impairment in patients suffering from a sleep disorder, particularly insomnia, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, for example, about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0313] The reduction or elimination of cognitive impairment 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.

[0314] Reduction or elimination of cognitive impairment in a patient suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in scores on at least Sleep Quality Score (SQS) items 15, 19, 21, and / or 22 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, where the recall time spans from the time the acute hallucinatory experience after the last administration subsided through the time of assessment.

[0315] The reduction or elimination of cognitive impairment in patients suffering from sleep disorders, particularly insomnia, as reflected by an improvement in scores on SQS items 15, 19, 21, and / or 22 occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of assessment. The reduction or elimination of cognitive impairment as reflected by an improvement in scores on SQS items 15, 19, 21, and / or 22 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, where the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of assessment.

[0316] Reduction or elimination of cognitive impairment in a patient suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in the score on at least Insomnia Severity Index (ISI) item 3 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, where the recall time spans from the time the acute hallucinatory experience after the last administration subsided through the time of assessment.

[0317] The reduction or elimination of cognitive impairment in patients suffering from sleep disorders, particularly insomnia, as reflected by an improvement in ISI Item 3 score occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of assessment. The reduction or elimination of cognitive impairment as reflected by an improvement in ISI Item 3 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, where the recall period extends from the time the acute hallucinatory experience after the last administration subsided to the time of assessment.

[0318] Reduction or elimination of cognitive impairment in a patient suffering from a sleep disorder, particularly insomnia, is reflected by 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0319] The reduction or elimination of cognitive impairment in a patient suffering from a sleep disorder, particularly insomnia, 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 impairment in a patient suffering from a sleep disorder, particularly insomnia, 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.

[0320] Reduction or elimination of cognitive impairment in patients suffering from a sleep disorder, particularly insomnia, is reflected by an improvement in one or more of the Matrix Consensus Cognitive Battery (MCCB) scores or component scores at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0321] The reduction or elimination of cognitive impairment 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 within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment 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.

[0322] As mentioned above, cognitive dysfunction is an important aspect in patients suffering from sleep disorder.Therefore, the improvement of cognitive dysfunction will also lead to the improvement of sleep disorder.In addition, because cognitive dysfunction also affects other aspects of sleep disorder, the inventors conclude that the observed improvement of cognitive dysfunction will additionally contribute to the overall improvement of sleep disorder, especially insomnia.

[0323] 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.

[0324] Improvement in the idiopathic sleep disorder, as reflected by a reduction in CGI-S score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0325] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0326] 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.

[0327] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by at least a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of "much improved," preferably occurs within about 24 hours of the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0328] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by at least a reduction in the CGI-I score or PGI-I score by a "much improved" score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0329] Improvement in the case of sleep disorders may also be assessed by any other scale that reflects changes in quality or quantity of sleep as described above, for example the Pittsburgh Sleep Quality Index (PSQI).

[0330] 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.

[0331] Improvement in sleep disturbance, as reflected by a decrease in PSQI score, particularly a decrease of 5 or less, preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins when the acute hallucinatory experience after the last administration subsides and extends through the time of assessment.

[0332] 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, wherein the recall time spans from the time the acute hallucinatory experience after the last administration subsided to the time of assessment.

[0333] Improvement in sleep disturbance, as reflected by a reduction 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, where recall time spans from the time the acute hallucinatory experience after the last administration subsided to the time of assessment.

[0334] Cognitive dysfunction and sleep disorders, especially insomnia, are closely related to psychiatric and nervous system disorders. Both cognitive dysfunction and sleep disorders, especially insomnia, are associated with disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder (SAD), and bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder); anxiety disorders, such as separation anxiety disorder, cyclophobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, and phobia, and substance / drug-induced anxiety disorder; somatic symptom disorder; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); somatoform disorders, such as body dysmorphic disorder (BDD); obsessive-compulsive disorder (OCD); posttraumatic stress disorder (PTSD); pain disorders, such as chronic pain, and fibromyalgia and migraine; mental and behavioral disorders resulting from the use of psychoactive substances, e.g., substance use disorders (SUDs); psychotic disorders, e.g., schizophrenia; Huntington's disease; Parkinson's disease; or schizotypal personality disorder; dementia, e.g., Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia; Parkinson's disease (PD); Huntington's disease (HD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, e.g., schizotypal personality disorder and borderline personality disorder; occurring in mental or nervous system disorders such as psychiatric or nervous system disorders associated with HIV, traumatic brain injury or post-COVID pathology.

[0335] Both cognitive impairment and sleep disorders, particularly insomnia, also occur in medical health conditions that lead to related psychiatric or neurological conditions, such as HIV, traumatic brain injury, or post-COVID pathology, and in unspecified neurocognitive dysfunction.

[0336] Treatment according to the present invention results in improvement of both cognitive impairment and sleep disorders, particularly insomnia, as well as improvement of associated psychiatric or nervous system disorders such as those listed above, as well as improvement of mental or nervous system conditions associated with specific medical conditions such as those exemplified above, and improvement of unspecified neurocognitive impairments.

[0337] Treatment of cognitive dysfunction, psychiatric disorders, and nervous system disorders In patients suffering from cognitive impairment associated with a psychiatric or nervous system disorder, treatment of the cognitive impairment according to the present invention leads to an improvement in the condition associated with the cognitive impairment.

[0338] Although cognitive impairment may be considered a medical condition worthy of treatment regardless of any other medical conditions, disorders, or symptoms that an individual may suffer from, some psychiatric disorders and nervous system disorders are associated with cognitive impairment. Notably, the relationship between cognitive impairment and psychiatric disorders is bidirectional. Not only can psychiatric disorders have a negative impact on cognitive function, but cognitive impairment may also contribute to the onset, progression, and prognosis of psychiatric disorders or nervous system disorders.

[0339] In many instances, the resting-state networks involved in cognitive dysfunction are also involved in the pathologies listed above.

[0340] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption resets pathologically unhealthy brain connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0341] A disorder characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0342] A depressive episode is a period of depressed mood and / or a lack of pleasure in most activities.

[0343] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms occurring during the same two-week period and presenting at least one of the following symptoms: a change from previous functioning; (1) depressed mood; or (2) loss of interest or pleasure.

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

[0345] Cognitive impairment 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.

[0346] Cognitive impairment is included in the diagnostic criteria for disorders characterized by depressive episodes and can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment.

[0347] 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.

[0348] The items are outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel emotions, pessimistic thoughts, and suicidal thoughts, and each item is given a score of 0 to 6. The total score ranges from 0 to 60.

[0349] Difficulty concentrating, described as difficulty organizing one's thoughts and a gradual loss of concentration until one is unable to function normally, is rated on a scale ranging from "no difficulty concentrating" (=0), "occasionally have difficulty organizing one's thoughts" (=1, 2 or 3), "difficulty concentrating and sustaining thoughts, and reduced ability to read or carry on a conversation" (=3, 4 or 5) to "unable to read or hold a conversation" (=6).

[0350] The Hamilton Rating Scale for Depression (HAM-D) allows clinicians to assess the nature and severity of mood disorders in a patient population. The scale contains 21 questionnaire items, but only the first 17 items (depressed mood, feelings of guilt, suicide, initial insomnia, nighttime insomnia, late insomnia, work and interest, retardation, agitation, psychiatric anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic symptoms, genital symptoms, hypochondriasis, weight loss, and insight) are used for scoring.

[0351] For most questions, scores range from 0 to 4, with 4 representing more severe signs of depression. Some questions only range down to 2. Total scores are tallied and may then be compared with previous scores or against a predefined cutoff score.

[0352] In the context of the item "retardation," the questionnaire assesses slowness of thought and speech, impaired concentration, and reduced motor activity.

[0353] The British Columbia Cognitive Complaints Inventory (BC-CCI) is a brief screening self-assessment tool that assesses perceived cognitive difficulties in patients with disorders characterized specifically by depressive episodes.

[0354] The scale consists of six items assessing perceived difficulties over the past seven days, including difficulty concentrating, remembering, expressing thoughts, word finding, slow thinking, and problem-solving. Scores for each item (ranging from 0 (not at all) to 3 (very much)) are summed to give a total score ranging from 0 to 18, with higher scores indicating greater severity of cognitive impairment.

[0355] Cognitive impairment in patients suffering from a disorder characterized by depressive episodes can be assessed using, for example, the Screen for Cognitive Impairment in Psychiatry (SCIP), the Montreal Cognitive Assessment (MoCA), or the Matrices Consensus Cognitive Battery (MCCB) score, or one or more of their component scores.

[0356] In patients suffering from disorders characterized by depressive episodes, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes related to processing, control, emotional memory, rumination, and impairments in concentration and physiological arousal.

[0357] Treating patients suffering from a treatment-resistant form of the disorder and a disorder characterized by depressive episodes with associated cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the disorder characterized by the depressive episodes.

[0358] The reduction or elimination of cognitive impairment in a patient suffering from a disorder characterized by a depressive episode is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] The reduction or elimination of cognitive impairment in a patient suffering from a disorder characterized by a depressive episode occurs within about 2 hours after the last administration of 5-MeO-DMT or a 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.

[0360] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the score for at least the difficulty concentrating MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0361] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0362] Reduction or elimination of cognitive impairment, particularly slowing, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the slowing score on at least the HAM-D item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0363] The reduction or elimination of cognitive impairment, particularly slowing, in a patient suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the HAM-D item slowing 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 impairment, as reflected by an improvement in the HAM-D item slowing 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.

[0364] Reduction or elimination of cognitive impairment in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0365] The reduction or elimination of cognitive impairment in a patient suffering from a disorder characterized by depressive episodes, 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 impairment, 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.

[0366] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from a disorder characterized by depressive episodes is reflected by an improvement in Montreal Cognitive Assessment (MoCA) score 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.

[0367] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient 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 impairment, particularly difficulty concentrating, in a patient suffering from a disorder characterized by depressive episodes 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.

[0368] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from a disorder characterized by a depressive episode is reflected by an improvement in one or more of the Matrix Consensus Cognitive Battery (MCCB) scores or component scores at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0369] The reduction or elimination of cognitive impairment, 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 within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, 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 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.

[0370] As mentioned above, cognitive dysfunction is closely related to the disorder characterized by depressive episodes.Therefore, improving cognitive dysfunction will also lead to the improvement of the disorder characterized by depressive episodes.In addition, because cognitive dysfunction also affects other aspects of the disorder characterized by depressive episodes, the inventors conclude that the improvement of cognitive dysfunction, particularly the reduction or disappearance of concentration difficulty, will additionally contribute to the overall improvement of the disorder characterized by depressive episodes.

[0371] Improvement in the disorder characterized by a depressive episode in a patient who also suffers from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] The improvement in the disorder characterized by a depressive episode in a patient who also suffers from an associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by a depressive episode in a patient who also suffers from an associated cognitive impairment, 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.

[0373] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest, which affects a person's feelings, thoughts, and behaviors and can lead to a variety of emotional and physical problems.

[0374] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder (TRD).

[0375] Cognitive impairment is common in patients with major depressive disorder (MDD) and is pervasive across several different cognitive domains, including memory, executive function, attention, and emotional processing.

[0376] 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 impairment is a major mediator of functional impairment, particularly through its impact on workplace performance. Attention impairments are particularly detrimental to daily functioning and are associated with poor clinical outcomes.

[0377] Cognitive dysfunction, especially the decline in the ability to think or concentrate, is included in the diagnostic criteria for MDD.Related cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention.Attention impairment negatively impacts daily functioning and is associated with poor clinical outcomes.Cognitive dysfunction is associated with disproportionately poor prognosis in psychosocial and occupational domains.

[0378] Cognitive impairment in patients with MDD can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment, which can be further assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP), Montreal Cognitive Assessment (MoCA), or Matrices Consensus Cognitive Battery (MCCB) scores, or scores on one or more of their components.

[0379] In patients with MDD, dysfunctional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, and executive control network, is observed, with functional connectivity significantly different from that observed in healthy controls.

[0380] More specifically, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes related to processing, control, emotional memory, rumination, and impairments in concentration and physiological arousal.

[0381] Treating patients suffering from MDD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the MDD.

[0382] The reduction or elimination of cognitive impairment in a patient with MDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0383] The reduction or elimination of cognitive impairment in a patient suffering from 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.

[0384] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from MDD is reflected by an improvement in the score for at least the difficulty concentrating MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0385] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from MDD, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0386] Reduction or elimination of cognitive impairment in a patient with MDD is reflected by an improvement in the HAM-D item retardation score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] The reduction or elimination of cognitive impairment in a patient with MDD, as reflected by an improvement in the HAM-D item slowness 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 impairment, as reflected by an improvement in the HAM-D item slowness 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] The reduction or elimination of cognitive impairment in a patient with MDD is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0389] The reduction or elimination of cognitive impairment in a patient with MDD, 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 impairment, 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.

[0390] The reduction or elimination of cognitive impairment in a patient with MDD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0391] The reduction or elimination of cognitive impairment in a patient with MDD, 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 impairment, 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.

[0392] The reduction or elimination of cognitive impairment in a patient with MDD is reflected by an improvement in at least one of the Matrix Consensus Cognitive Battery (MCCB) scores or component scores at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0393] The reduction or elimination of cognitive impairment in a patient with MDD, as reflected by an improvement in the MCCB score or one or more of its component scores, 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 impairment, 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.

[0394] As mentioned above, cognitive dysfunction is closely related to MDD.Therefore, improving cognitive dysfunction will also lead to the improvement of MDD.In addition, cognitive dysfunction also affects other aspects of MDD, so we conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will additionally contribute to the overall improvement of MDD.

[0395] Improvement in MDD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0396] Improvement in MDD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0397] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks of giving birth. More than 50% of women experience a short period of low mood or tearfulness after giving birth, and some women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0398] Patients with PPD may suffer from a treatment-resistant form of the disorder.

[0399] PPD also affects cognition, with many PPD patients frequently complaining of memory loss that interferes with daily activities.

[0400] Depression during the postpartum period not only affects the mother's overall well-being, but also how she interacts with her child and therefore how that child develops.

[0401] Cognitive impairment in patients with PPD can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment, which can be further assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP), Montreal Cognitive Assessment (MoCA), or Matrices Consensus Cognitive Battery (MCCB) scores, or scores on one or more of their components.

[0402] 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 connectivity within and / or between resting-state networks, such as the default mode network and the frontoparietal network.

[0403] Treating patients suffering from PPD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the PPD.

[0404] The reduction or elimination of cognitive impairment in a patient with PPD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0405] The reduction or elimination of cognitive impairment in a patient suffering from 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.

[0406] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient with PPD is reflected by an improvement in the score for at least the difficulty concentrating MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0407] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from PPD, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0408] Reduction or elimination of cognitive impairment in a patient with PPD is reflected by an improvement in the HAM-D item retardation score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0409] The reduction or elimination of cognitive impairment in a patient with PPD, as reflected by an improvement in the HAM-D item slowness 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 impairment, as reflected by an improvement in the HAM-D item slowness 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.

[0410] Reduction or elimination of cognitive impairment in a patient with PPD is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0411] The reduction or elimination of cognitive impairment in a patient with PPD, 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, 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.

[0412] The reduction or elimination of cognitive impairment in a patient with PPD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0413] The reduction or elimination of cognitive impairment in a patient 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 impairment, 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.

[0414] Reduction or elimination of cognitive impairment in a patient with PPD is reflected by an improvement in at least one of the Matrix Consensus Cognitive Battery (MCCB) scores or component scores at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0415] The reduction or elimination of cognitive impairment in a patient with PPD, as reflected by an improvement in the MCCB score or one or more of its component scores, 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 impairment, 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.

[0416] As mentioned above, cognitive dysfunction is closely related to PPD.Therefore, the improvement of cognitive dysfunction will also lead to the improvement of PPD.In addition, cognitive dysfunction also affects other aspects of PPD, so we conclude that the improvement of cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will additionally contribute to the overall improvement of PPD.

[0417] Improvement in PPD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0418] The improvement in PPD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0419] Furthermore, cognitive impairment impairs maternal function.

[0420] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF), which is designed to measure functioning over the course of the year following delivery. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6 for a maximum total score of 120. Higher scores indicate better maternal functioning.

[0421] The BIMF identifies the primary functional domains of mothers during the postnatal period: self-care, infant care, mother-infant communication, maternal emotional well-being, social support, control, and adjustment.

[0422] A BIMF of 95 or less is considered herein to represent slightly impaired maternal function, a score of 80 or less is considered herein to represent impaired maternal function, and a score of 65 or less is considered herein to represent severely impaired maternal function.

[0423] The inventors determined that an increase in the score on the MADRS item "Difficulty concentrating" negatively impacts maternal functioning (maternal receptiveness in communicating with infant(s) as well as maternal self-care).

[0424] An increase in the score for the MADRS item "Difficulty concentrating" impairs infant care and management. Conversely, an improvement on this MADRS item leads to an improvement in maternal functioning, particularly the infant care and / or management of the BIMF functional domain.

[0425] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improved cognitive function, particularly a reduction or elimination of concentration difficulties.

[0426] We further conclude that the reduction or elimination of concentration difficulties by treating PPD patients not only results in a reduction in the MADRS total score, but also in improved maternal functioning as reflected by improved BIMF scores.

[0427] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0428] Improvement in maternal function in patients with PPD is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0429] Improvement in maternal function in patients with PPD, as reflected by an improvement in the BIMF total score, occurs within 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.

[0430] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. Persistent depressive disorder is diagnosed when a person experiences depressed moods for most of the day for at least two years, with symptom-free periods of less than two months.

[0431] During a depression, two or more of the following are present: 1. feelings of hopelessness, 2. low energy or fatigue, 3. low self-esteem, 4. decreased sleep (insomnia) or increased sleep (hypersomnia), 5. loss of appetite or overeating, 6. difficulty making decisions or concentrating.

[0432] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0433] Cognitive impairment is common in patients with persistent depressive disorder and is pervasive across several different cognitive domains, including memory, executive function, attention, and emotional processing.

[0434] 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 impairment is a major mediator of functional impairment, particularly through its impact on workplace performance. Attention impairments particularly negatively impact daily functioning and are associated with poor clinical outcomes.

[0435] Cognitive dysfunction is included in the diagnostic criteria of persistent depressive disorder, especially in the decline of the ability to think or concentrate.Related cognitive problems include impairments in executive function, learning and memory, processing speed, and concentration and attention.Attention impairment has a negative impact on daily function and is associated with poor clinical outcomes.Cognitive dysfunction is associated with disproportionately poor prognosis in psychosocial and occupational domains.

[0436] Cognitive impairment in patients with persistent depressive disorder can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment, which can be further assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP), Montreal Cognitive Assessment (MoCA), or Matrices Consensus Cognitive Battery (MCCB) scores, or scores on one or more of their components.

[0437] In patients with persistent depressive disorder, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, and impaired concentration and physiological arousal. Dysfunctions in connectivity and regulation are observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0438] Treatment of patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the persistent depressive disorder.

[0439] The reduction or elimination of cognitive impairment in patients with persistent depressive disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0440] The reduction or elimination of cognitive impairment in a patient suffering from 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.

[0441] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from persistent depressive disorder is reflected by an improvement in the score for at least the difficulty concentrating item on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0442] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from persistent depressive disorder, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0443] Reduction or elimination of cognitive impairment in a patient suffering from persistent depressive disorder is reflected by an improvement in at least the HAM-D item retardation score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0444] The reduction or elimination of cognitive impairment in patients with persistent depressive disorder, as reflected by an improvement in the HAM-D item retardation 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 impairment, as reflected by an improvement in the HAM-D item retardation 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.

[0445] The reduction or elimination of cognitive impairment in a patient suffering from persistent depressive disorder is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0446] The reduction or elimination of cognitive impairment in patients with persistent depressive 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 impairment, 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.

[0447] The reduction or elimination of cognitive impairment in a patient suffering from persistent depressive disorder is reflected by an improvement in the score on at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] The reduction or elimination of cognitive impairment 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 impairment, 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.

[0449] The reduction or elimination of cognitive impairment in a patient with persistent depressive disorder is reflected by an improvement in at least one of the scores on the Matrix Consensus Cognitive Battery (MCCB) score or its components at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] The reduction or elimination of cognitive impairment in a patient suffering from persistent depressive disorder, as reflected by an improvement in the MCCB score or one or more of its component scores, 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 impairment, 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.

[0451] As mentioned above, cognitive dysfunction is closely related to persistent depressive disorder.Therefore, the improvement of cognitive dysfunction will also lead to the improvement of persistent depressive disorder.In addition, cognitive dysfunction also affects other aspects of persistent depressive disorder, so the inventors conclude that the improvement of cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will additionally contribute to the overall improvement of persistent depressive disorder.

[0452] Improvement in persistent depressive disorder in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] The improvement in persistent depressive disorder in a patient who also suffers from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in persistent depressive disorder in a patient who also suffers from associated cognitive impairment, 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.

[0454] 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.

[0455] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0456] The cognitive dysfunction associated with seasonal affective disorder may affect concentration, perception, attention, or memory.Importantly, in patients with seasonal affective disorder, cognition is impaired not only in winter but also in summer.Compared with control subjects, patients with seasonal affective disorder show significant season-independent impairments in tasks measuring working memory, cognitive processing speed, and motor speed.

[0457] Cognitive impairment in patients with seasonal affective disorder can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment, which can be further assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP), Montreal Cognitive Assessment (MoCA), or Matrices Consensus Cognitive Battery (MCCB) scores, or scores on one or more of their components.

[0458] Altered functional connectivity within and / or between resting-state networks associated with visual, sensorimotor, and attentional processing was detected in patients with seasonal affective disorder compared to 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 processes.

[0459] Treating patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the seasonal affective disorder.

[0460] The reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0461] The reduction or elimination of cognitive impairment 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.

[0462] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from seasonal affective disorder is reflected by an improvement in the score for at least the difficulty concentrating item on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0463] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient suffering from seasonal affective disorder, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0464] Reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder is reflected by an improvement in the HAM-D item retardation score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0465] The reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder, as reflected by an improvement in the HAM-D item slowness 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 impairment, as reflected by an improvement in the HAM-D item slowness 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 impairment in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0467] The reduction or elimination of cognitive impairment in a patient suffering from 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 impairment, 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 impairment in a patient suffering from seasonal affective disorder is reflected by an improvement in the score on at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0469] The reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder, 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 impairment, 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.

[0470] The reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder is reflected by an improvement in at least one of the scores on the Matrix Consensus Cognitive Battery (MCCB) score or its components at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at day 1, e.g., about 24 hours, at day 7, at day 14, and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0471] The reduction or elimination of cognitive impairment in a patient suffering from seasonal affective disorder, as reflected by an improvement in the MCCB score or one or more of its component scores, 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 impairment, 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 seasonal affective disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of seasonal affective disorder.In addition, cognitive dysfunction also affects other aspects of seasonal affective disorder, so the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration difficulty, will additionally contribute to the overall improvement of seasonal affective disorder.

[0473] Improvement in seasonal affective disorder in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] Improvement in seasonal affective disorder in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder in patients who also suffer from associated cognitive impairment, 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.

[0475] 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.

[0476] 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.

[0477] Patients with BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0478] In BD, which includes bipolar I disorder and bipolar II disorder, cognitive impairments are present during periods of severe emotional states, as well as periods of euthymia.

[0479] Cognitive impairment in BD is seen across multiple domains, particularly in language and working memory, attention, and executive function.

[0480] Cognitive impairment in patients with BD can be assessed by the British Columbia Cognitive Complaints Inventory (BC-CCI) or as part of the HAM-D or MADRS assessment, which can be further assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP), Montreal Cognitive Assessment (MoCA), or Matrices Consensus Cognitive Battery (MCCB) scores, or scores on one or more of their components.

[0481] 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 assess the severity of depressive and / or mixed symptoms exhibited by patients during the current and past few days based on a clinical interview. 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 score of 60. Higher scores indicate greater severity.

[0482] 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.

[0483] Each of these aspects is evaluated and assigned a score of 0, 1, 2 or 3.

[0484] Concentration and memory impairments are 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 significant impairment in concentration or memory and considerable impairment (e.g., inability to read or watch television).

[0485] Patients suffering from bipolar disorder exhibit characteristic abnormal intrinsic organization and interconnectivity of resting-state networks.

[0486] Compared to healthy controls, resting-state functional magnetic resonance imaging studies revealed altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network.

[0487] Treating patients suffering from BD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and leads to improvement of BD.

[0488] The reduction or elimination of cognitive impairment in a patient with BD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] The reduction or elimination of cognitive impairment in a patient 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.

[0490] Reduction or elimination of cognitive impairment, particularly impairment in concentration and memory, in a patient with BD is reflected by an improvement in at least the impairment in concentration and memory scores on the BDRS items about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0491] The reduction or elimination of cognitive impairment, particularly impairment in concentration and memory, in patients with BD, as reflected by an improvement in the BDRS impairment in concentration and memory scores occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0492] The reduction or elimination of cognitive impairment, particularly impairment of concentration and memory, as reflected by an improvement in the BDRS item concentration and memory impairment 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] Reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient with BD is reflected by an improvement in the score for at least the difficulty concentrating item on the MADRS item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] The reduction or elimination of cognitive impairment, particularly difficulty concentrating, in a patient with BD, as reflected by an improvement in the difficulty concentrating score on the MADRS item, 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 impairment, particularly difficulty concentrating, as reflected by an improvement in the difficulty concentrating score on the MADRS 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.

[0495] Reduction or elimination of cognitive impairment in a patient with BD is reflected by an improvement in the HAM-D item retardation score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0496] The reduction or elimination of cognitive impairment in a patient with BD, as reflected by an improvement in the HAM-D item slowness 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 impairment, as reflected by an improvement in the HAM-D item slowness 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.

[0497] Reduction or elimination of cognitive impairment in a patient with BD is reflected by an improvement in the score on at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] The reduction or elimination of cognitive impairment in patients with BD, 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, 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.

[0499] Reduction or elimination of cognitive impairment in a patient with BD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0500] The reduction or elimination of cognitive impairment 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 impairment, 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.

[0501] Reduction or elimination of cognitive impairment in a patient with BD is reflected by an improvement in at least one of the Matrix Consensus Cognitive Battery (MCCB) scores or component scores at about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] The reduction or elimination of cognitive impairment in a patient with BD, as reflected by an improvement in the MCCB score or one or more of its component scores, 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 impairment, 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.

[0503] As mentioned above, cognitive dysfunction is closely related to BD.Therefore, improving cognitive dysfunction will also lead to the improvement of BD.In addition, cognitive dysfunction also affects other aspects of BD, so the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration difficulty, will additionally contribute to the overall improvement of BD.

[0504] Improvement in BD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0505] Improvement in BD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0506] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include feelings of nervousness, panic and fear, as well as sweating and rapid heartbeat. Anxiety affects complex cognitive, emotional, physiological, and behavioral response systems involved in preparing for anticipated events or situations that are perceived as threatening.

[0507] Patients suffering from anxiety disorders may suffer from treatment-resistant forms of the disorder.

[0508] Several domains of cognitive function, including spatial working memory, executive function, and attentional biases, are dysregulated in anxiety states and disorders in general.

[0509] 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 psychological distress) and somatic anxiety (physical complaints related to anxiety). Item 5 is "intellect," defined as "poor concentration and memory." Each item is scored on a scale from 0 (none) to 4 (severe), with a total score ranging from 0 to 56, where <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe severity.

[0510] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0511] Anxiety disorders are studied by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). Furthermore, the networks affected by these disorders are the salience network (SN) and the somatomotor network (SMN). The resting balance within and / or between these networks, such as the DMN and the associated SMN and SN, may be abnormal in different anxiety disorders.

[0512] Treating patients suffering from anxiety disorders, including treatment-resistant forms of the disorders and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the anxiety disorder.

[0513] The reduction or elimination of cognitive impairment 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0514] The reduction or elimination of cognitive impairment 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.

[0515] Reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from an anxiety disorder is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0516] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from an anxiety disorder, as reflected by an improvement in the "Intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "Intelligence" score on the HAM-A 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.

[0517] The reduction or elimination of cognitive impairment in a patient suffering from an anxiety disorder is reflected by an improvement in at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0518] The reduction or elimination of cognitive impairment in a patient suffering from an 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 impairment, 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.

[0519] The reduction or elimination of cognitive impairment in a patient suffering from an anxiety disorder is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0520] The reduction or elimination of cognitive impairment in a patient suffering from an anxiety disorder, 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 impairment, 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.

[0521] As mentioned above, cognitive dysfunction is closely related to anxiety disorder.Therefore, improving cognitive dysfunction will also lead to the improvement of anxiety disorder.In addition, cognitive dysfunction also affects other aspects of anxiety disorder, so the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration deficit and memory impairment, will additionally contribute to the overall improvement of anxiety disorder.

[0522] Improvement in anxiety disorders in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0523] The improvement in the anxiety disorder in a patient who also suffers from an associated cognitive impairment, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the anxiety disorder in a patient who also suffers from an associated cognitive impairment, 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.

[0524] Separation anxiety disorder is characterized by excessive anxiety about separation from home and / or people to whom the patient feels strong emotional attachment.

[0525] Separation situations can cause significant distress for patients, and the separation can make it difficult for them to attend school or work. Patients with separation anxiety disorder may also experience excessive anxiety about unpleasant events that occur to important people in their lives, such as family members.

[0526] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0527] Several domains of cognitive function, including spatial working memory, executive function, and attentional biases, are dysregulated in anxiety states and disorders in general.

[0528] Assessment of cognitive impairment is part of the Hamilton Anxiety Rating Scale (HAM-A). Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0529] Functional magnetic resonance imaging of individuals suffering from separation anxiety disorder reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0530] Treating patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the separation anxiety disorder.

[0531] The reduction or elimination of cognitive impairment 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0532] The reduction or elimination of cognitive impairment 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.

[0533] Reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from separation anxiety disorder is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0534] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from separation anxiety disorder, as reflected by an improvement in the "Intelligence" score on the HAM-A item 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 impairment, particularly concentration and memory impairment, as reflected by an improvement in the "Intelligence" score on the HAM-A 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.

[0535] Reduction or elimination of cognitive impairment in a patient suffering from separation anxiety disorder is reflected by an improvement in at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0536] The reduction or elimination of cognitive impairment in a patient suffering from 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 impairment, 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.

[0537] The reduction or elimination of cognitive impairment in a patient suffering from separation anxiety disorder is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0538] The reduction or elimination of cognitive impairment in a patient suffering from separation anxiety disorder, 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 impairment, 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.

[0539] 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.In addition, cognitive dysfunction also affects other aspects of separation anxiety disorder, so the inventors conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration deficit and memory impairment, will additionally contribute to the overall improvement of separation anxiety disorder.

[0540] Improvement in separation anxiety disorder in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0541] Improvement in separation anxiety disorder in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0542] Acrophobia is the fear of situations or places that can cause feelings of panic, oppression, helplessness, or embarrassment.

[0543] Patients suffering from acrophobia may find it difficult to leave the house. The thought of leaving the house can cause considerable anxiety to the point of avoidance. Fear of crowds, travel, elevators, cinemas, malls, etc. can cause significant problems.

[0544] Patients with acrophobia may also experience recurrent panic attacks.

[0545] Patients suffering from acrophobia may suffer from a treatment-resistant form of the disorder.

[0546] Several domains of cognitive function, including spatial working memory, executive function, and attentional biases, are dysregulated in anxiety states and disorders in general.

[0547] Assessment of cognitive impairment is part of the Hamilton Anxiety Rating Scale (HAM-A). Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0548] Functional magnetic resonance imaging of individuals with acrophobia reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0549] Treating patients suffering from acrophobia, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of acrophobia.

[0550] The reduction or elimination of cognitive impairment in a patient suffering from acrostrophobia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0551] The reduction or elimination of cognitive impairment in a patient suffering from acrophobia 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.

[0552] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from acrostrophobia is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0553] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in patients suffering from acrostrophobia, as reflected by an improvement in the "intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "intelligence" score on the HAM-A 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.

[0554] The reduction or elimination of cognitive impairment in a patient suffering from acrostrophobia is reflected by an improvement in at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0555] The reduction or elimination of cognitive impairment in a patient suffering from acrophobia, 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, 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.

[0556] The reduction or elimination of cognitive impairment in a patient suffering from acrophobia is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] The reduction or elimination of cognitive impairment in a patient suffering from acrophobia, 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 impairment, 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.

[0558] As mentioned above, cognitive dysfunction is closely related to acrophobia. Therefore, the improvement of cognitive dysfunction will also lead to the improvement of acrophobia. Furthermore, because cognitive dysfunction also affects other aspects of acrophobia, the inventors conclude that the improvement of cognitive dysfunction, particularly the reduction or elimination of concentration deficit and memory decline, will additionally contribute to the overall improvement of acrophobia.

[0559] Improvement in acrophobia in a patient who also suffers from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] The improvement in acrophobia in a patient who also suffers from an associated cognitive impairment, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in acrophobia in a patient who also suffers from an associated cognitive impairment, 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.

[0561] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control anxiety about a wide range of situations and problems. Patients with GAD may anticipate disasters and may worry excessively about money, health, family, work, or other issues.

[0562] Generalized anxiety disorder is diagnosed when an individual experiences persistent anxiety about everyday challenges that is disproportionate to the perceived threat. GAD patients typically experience excessive fear that can last for months to years.

[0563] GAD interferes with social, occupational, or other important areas of functioning.

[0564] Patients with GAD may suffer from a treatment-resistant form of the disorder.

[0565] Patients with GAD report at least three of the following six symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbances.

[0566] Elderly patients with GAD exhibit poorer cognitive function, particularly poorer short-term memory, when compared with non-anxious age-matched individuals.

[0567] Impairments in general cognition as well as inductive reasoning and inhibition have been found to be risk factors for the development of GAD in older adults.

[0568] Difficulty concentrating is thought to be one mechanism by which anxiety increases its clinical severity. Difficulty concentrating causes significant distress and impairment in role functioning.

[0569] Assessment of cognitive impairment is part of the DSM-5 Generalized Anxiety Disorder questionnaire and the Hamilton Anxiety Rating Scale (HAM-A). Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0570] GAD patients also exhibit altered functional connectivity, particularly within the default mode network.

[0571] Treating patients suffering from GAD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of GAD.

[0572] The reduction or elimination of cognitive impairment in a patient with GAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0573] The reduction or elimination of cognitive impairment in a patient 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.

[0574] Reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient with GAD is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0575] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from GAD, as reflected by an improvement in the "Intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "Intelligence" score on the HAM-A 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.

[0576] The reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient with GAD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0577] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient with GAD, 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 impairment, particularly concentration and memory impairment, 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.

[0578] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient with GAD is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0579] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient with GAD, 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 impairment, particularly concentration and memory impairment, 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.

[0580] As mentioned above, cognitive dysfunction is closely related to GAD.Therefore, improving cognitive dysfunction will also lead to improving GAD.In addition, cognitive dysfunction also affects other aspects of GAD, so the inventors conclude that improving cognitive dysfunction, especially the reduction or elimination of concentration deficit and memory impairment, will additionally contribute to the overall improvement of GAD.

[0581] Improvement in GAD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0582] The improvement in GAD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0583] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety.

[0584] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations, which often leads to withdrawal from social situations and can cause school, work, or relationship impairments.

[0585] Patients with SAD may suffer from a treatment-resistant form of the disorder.

[0586] Cognitive impairment is also associated with SAD.

[0587] Several domains of cognitive function, including spatial working memory, executive function, and attentional biases, are dysregulated in anxiety states and disorders in general.

[0588] Assessment of cognitive impairment is part of the Hamilton Anxiety Rating Scale (HAM-A). Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0589] 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 predominantly found in the DMN and SN.

[0590] Treating patients suffering from SAD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of SAD.

[0591] The reduction or elimination of cognitive impairment in a patient with SAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0592] The reduction or elimination of cognitive impairment in a patient 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.

[0593] Reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from SAD is reflected by an improvement in at least the "Intelligence" score on the HAM-A item about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0594] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from SAD, as reflected by an improvement in the "Intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "Intelligence" score on the HAM-A 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.

[0595] The reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from SAD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0596] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from SAD, 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 impairment, particularly concentration and memory impairment, 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.

[0597] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient with SAD is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0598] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in patients with SAD, 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 impairment, particularly concentration and memory impairment, 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.

[0599] As mentioned above, cognitive dysfunction is closely related to SAD.Therefore, improving cognitive dysfunction will also lead to the improvement of SAD.In addition, cognitive dysfunction also affects other aspects of SAD, so we conclude that improving cognitive dysfunction, especially the reduction or disappearance of concentration deficit and memory impairment, will additionally contribute to the overall improvement of SAD.

[0600] Improvement in SAD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] Improvement in SAD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in SAD in patients who also suffer from associated cognitive impairment, 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.

[0602] Patients suffering from panic disorder experience spontaneous panic attacks, which involve sudden onset of intense fear or discomfort that peaks within minutes.

[0603] Panic attacks are characterized by symptoms that translate into many physical symptoms of anxiety, including sweating, trembling, shaking, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0604] Additionally, the disorder may often be characterized by anxiety about future panic attacks; patients may become preoccupied with fear of recurrent attacks.

[0605] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0606] Several domains of cognitive function, including spatial working memory, executive function, and attentional bias, are dysregulated in anxiety states and disorders in general. Panic disorder patients have been found to have abnormal initial processing of stimuli, manifested as increased startle responses and decreased habituation, when compared to non-panic disorder individuals.

[0607] Impaired memory function is a characteristic observed in patients with panic disorder.

[0608] Cognitive impairment can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A), one of the first rating scales developed to measure the severity of anxiety symptoms.

[0609] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0610] Panic disorder patients exhibit altered functional connectivity within and / or between the default mode network and the somatomotor network.

[0611] Functional magnetic resonance imaging of anxiety disorders reveals abnormalities in the default mode network (DMN), salience network (SN), and somatomotor / sensorimotor network (SMN). Resting-state balance within and / or between these networks, e.g., the DMN and associated SMN and SN, may be abnormal in different anxiety disorders.

[0612] Treating patients suffering from panic disorder, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the panic disorder.

[0613] The reduction or elimination of cognitive impairment in a patient suffering from panic disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0614] The reduction or elimination of cognitive impairment in a patient 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.

[0615] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from panic disorder is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0616] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from panic disorder, as reflected by an improvement in the "intelligence" score on the HAM-A item 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 impairment, particularly concentration and memory impairment, as reflected by an improvement in the "intelligence" score on the HAM-A 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.

[0617] The reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from panic disorder is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from panic 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 impairment, particularly concentration and memory impairment, 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.

[0619] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from panic disorder is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0620] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from panic 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 impairment, particularly concentration and memory impairment, 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.

[0621] As mentioned above, cognitive dysfunction is closely related to panic disorder.Therefore, the improvement of cognitive dysfunction will also lead to the improvement of PD.In addition, because cognitive dysfunction also affects other aspects of panic disorder, the inventors conclude that the improvement of cognitive dysfunction, especially the reduction or elimination of concentration deficit and memory impairment, will additionally contribute to the overall improvement of panic disorder.

[0622] Improvement in panic disorder in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0623] The improvement in panic disorder in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in panic disorder in patients who also suffer from associated cognitive impairment, 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.

[0624] A phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation.

[0625] Patients suffering from phobias experience excessive anxiety when they anticipate or are exposed to the feared stimulus. These include animal-type (spiders, snakes, dogs) phobias, environmental-type (tornadoes, heights, water, fire) phobias, blood-injection-type (needles, medical procedures) phobias, situational-type (flying in airplanes, enclosed spaces) phobias, and other types of phobias (phobias that do not fit into any of the above categories).

[0626] Phobias typically result in a rapid onset of fear, usually lasting for six months or more. Patients go to great lengths to avoid the feared stimulus. The fear and avoidance cause significant distress and / or impairment of occupational, academic, or social functioning.

[0627] Patients suffering from phobias may suffer from treatment-resistant forms of the disorder.

[0628] Cognitive dysfunction in phobias can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A).

[0629] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0630] For example, successful treatment, such as cognitive-behavioral treatment, tends to normalize abnormalities.

[0631] In individuals with specific phobia, the amygdala, anterior cingulate cortex (ACC), and insular cortex all appear to exhibit abnormally strong responses to specific phobia-related stimuli. For example, functional neuroimaging studies have identified the dorsal anterior cingulate cortex (dACC), which is part of the salience network, as exhibiting abnormally strong responses to phobia-related stimuli or the anticipation of such stimuli.

[0632] Treating patients suffering from phobias, including treatment-resistant forms of the disorders and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the phobia.

[0633] The reduction or elimination of cognitive impairment 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, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0634] The reduction or elimination of cognitive impairment 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.

[0635] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from a phobia is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0636] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from a phobia, as reflected by an improvement in the "intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "intelligence" score on the HAM-A 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.

[0637] The reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from a phobia is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0638] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from a phobia, 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 impairment, particularly concentration and memory impairment, 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.

[0639] The reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from a phobia is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the 1st day, e.g., about 24 hours, on the 7th day, on the 14th day, and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0640] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from a phobia, 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 impairment, particularly concentration and memory impairment, 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.

[0641] As mentioned above, cognitive dysfunction is closely related to phobia. Therefore, improvement of cognitive dysfunction will also lead to improvement of phobia. Furthermore, because cognitive dysfunction also affects other aspects of phobia, the inventors conclude that improvement of cognitive dysfunction, especially reduction or elimination of concentration deficit and memory decline, will additionally contribute to the overall improvement of phobia.

[0642] Improvement in phobia in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] The improvement in phobia in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0644] Substance / drug-induced anxiety disorder is an anxiety disorder in which anxiety or panic occurs after use of alcohol, drugs of abuse, or medication, or after exposure to a toxin. Substance / drug-induced anxiety disorder results in prominent symptoms of panic or anxiety and may occur during the intoxication or withdrawal phase of substance or drug use.

[0645] The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0646] While taking the substance or drug, or within a short time afterwards, an individual suffering from substance / drug-induced anxiety disorder may feel anxious or worried, experience symptoms of negative thinking, may have difficulty concentrating or remembering things, may feel fear of losing control or becoming confused or dying, may lose weight due to gastrointestinal problems, may feel chills, hot flashes, sweating, shaking, numbness, or a racing heart, difficulty breathing, swallowing, or chest pain.

[0647] Patients suffering from substance / drug-induced anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0648] Several domains of cognitive function, including spatial working memory, executive function, and attentional biases, are dysregulated in anxiety states and disorders in general.

[0649] Cognitive impairment can be directly assessed by the Hamilton Anxiety Rating Scale (HAM-A), one of the first rating scales developed to measure the severity of anxiety symptoms.

[0650] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0651] Functional magnetic resonance imaging of individuals suffering from substance / drug-induced anxiety disorders reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0652] Treating patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the substance / drug-induced anxiety disorder.

[0653] The reduction or elimination of cognitive impairment in a patient 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0654] The reduction or elimination of cognitive impairment in a patient suffering from 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.

[0655] Reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from substance / drug-induced anxiety disorder is reflected by an improvement in the score for at least the "Intelligence" item on the HAM-A at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0656] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from substance / drug-induced anxiety disorder, as reflected by an improvement in the "Intelligence" score on the HAM-A item occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, as reflected by an improvement in the "Intelligence" score on the HAM-A 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.

[0657] Reduction or elimination of cognitive impairment in a patient suffering from a substance / drug-induced anxiety disorder is reflected by an improvement in at least the Screen for Cognitive Impairment in Psychiatry (SCIP) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0658] The reduction or elimination of cognitive impairment in a patient suffering from substance / drug-induced 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 impairment, 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.

[0659] The reduction or elimination of cognitive impairment in a patient suffering from a substance / drug-induced anxiety disorder is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] The reduction or elimination of cognitive impairment in patients with 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 impairment, 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.

[0661] 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.In addition, because 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 deficit and memory impairment, will additionally contribute to the overall improvement of substance / drug-induced anxiety disorder.

[0662] Improvement in substance / drug-induced anxiety disorder in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0663] Improvement in substance / drug-induced anxiety disorder in patients who also suffer from associated cognitive impairment, as reflected by a reduction in CGI-S score, occurs within 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 who also suffer from associated cognitive impairment, 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.

[0664] somatic symptom disorder Somatic symptom disorder is a psychiatric disorder diagnosed when a person is markedly focused on physical symptoms, such as pain, weakness, or shortness of breath, to the point that they cause significant distress and / or problems with functioning and / or disrupt daily life. Illness-related sensations and behaviors are excessive or disproportionate.

[0665] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorder, the impairment is noticeable and, if persistent, can lead to debilitating conditions.

[0666] 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 associated with physical illness (possibly with catastrophic interpretations), leading to worries about illness and fears that any physical activity may result in bodily injury. Associated accompanying behavioral features may include repeated physical checking for abnormalities, repeated seeking of medical help and reassurance, and avoidance of physical activity.

[0667] Somatic symptom disorder can be assessed by the DSM-5 Level 2 - Somatic Symptoms - Adult scale. The scale includes 15 somatic symptoms. Respondents are asked to rate the severity of their personal somatic symptoms over the past seven days. Scoring ranges from "0" (not at all bothersome), "1" (slightly bothersome), to "2" (very bothersome). Total scores can range from 0 to 30, with higher scores indicating greater somatic symptom severity. Cutoff values ​​of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0668] The Somatic Symptom Disorder-B Criteria Scale (SSD-12) is also available. 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 = frequently). Ratings are summed to produce a simple total score, which can vary between 0 and 48 points. Alterations in attention are assessed by the items "Because of my physical complaints, I have difficulty concentrating on other tasks" or "My physical complaints take up most of my day."

[0669] Additionally, cognitive impairment in individuals with SSD can be assessed using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA).

[0670] Brain functional connectivity analysis reveals alterations within and / or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Alterations have been 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.

[0671] Treating patients suffering from somatic symptom disorder and associated cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the somatic symptom disorder.

[0672] The reduction or elimination of cognitive impairment in patients with somatic symptom disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0673] The reduction or elimination of cognitive impairment in a patient suffering from 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 impairment in a patient suffering from 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.

[0674] Reduction or elimination of cognitive impairment in a patient suffering from somatic symptom disorder is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] The reduction or elimination of cognitive impairment in patients with 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 impairment, 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.

[0676] The reduction or elimination of cognitive impairment in a patient suffering from somatic symptom disorder is reflected by an improvement in at least the Mini-Mental State Examination (MMSE) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0677] The reduction or elimination of cognitive impairment in patients with 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 impairment, 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.

[0678] As mentioned above, cognitive impairment and somatic symptom disorder are closely related. Therefore, improvement of cognitive impairment will also lead to improvement of somatic symptom disorder. Furthermore, because cognitive impairment affects other aspects of somatic symptom disorder, the inventors conclude that improvement of cognitive function will additionally contribute to an overall improvement of somatic symptom disorder.

[0679] Improvement in somatic symptom symptoms in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0680] The improvement in somatic symptom symptoms in patients who also suffer from an associated cognitive impairment, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in somatic symptom symptoms in patients who also suffer from an associated cognitive impairment, 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.

[0681] Obsessive-Compulsive and Related Disorders Obsessive-compulsive disorder (OCD) is a mental illness characterized by recurring, unwanted thoughts or sensations (obsessions) or repeated urges to do something (compulsions). Patients may suffer from both obsessions and compulsions.

[0682] Patients with OCD may suffer from treatment-resistant forms of the disorder.

[0683] Patients with OCD exhibit widespread dysfunction across multiple cognitive domains, including memory, attention, executive function, and language. Because cognitive resources are engaged in obsessions, patients may exhibit reduced cognitive flexibility during task performance.

[0684] Cognitive impairment can be assessed by the 13-item Cognitive Assessment Instrument of Obsessions and Compulsions (CAIOC-13), originally developed to investigate 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.

[0685] The CAIOC-13 examines 13 cognitive domains related to psychosocial impairments in OCD: (1) reading difficulties, (2) doubt, (3) fatigue, (4) sluggishness, (5) indecisiveness, (6) perfectionism, (7) circadian rhythm, (8) anxiety, (9) procrastination, (10) flexibility, (11) executive function, (12) anxiety about the future, and (13) compulsions.

[0686] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0687] Underlying neurobiological differences explain various forms of cognitive impairment in OCD patients compared to healthy age-matched individuals. Neuroimaging studies using functional magnetic resonance imaging in patients with OCD show altered functional connectivity within and / or between the frontoparietal network, the salience network, and the default mode network.

[0688] Treating patients suffering from OCD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the OCD.

[0689] The reduction or elimination of cognitive impairment 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0690] The reduction or elimination of cognitive impairment 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.

[0691] The reduction or elimination of cognitive impairment in a patient suffering from OCD is reflected by an improvement in the CAIOC-13 score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0692] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from OCD, as reflected by an improvement in CAIOC-13 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 impairment, particularly concentration and memory impairment, 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.

[0693] The reduction or elimination of cognitive impairment, particularly concentration deficits and memory decline, in a patient suffering from OCD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from OCD, 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 impairment, particularly concentration and memory impairment, 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.

[0695] Reduction or elimination of cognitive impairment, particularly concentration problems and memory decline, in a patient suffering from OCD is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] The reduction or elimination of cognitive impairment, particularly concentration and memory impairment, in a patient suffering from OCD, 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 impairment, particularly concentration and memory impairment, 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.

[0697] As mentioned above, cognitive dysfunction is closely related to OCD.Therefore, improving cognitive dysfunction will also lead to the improvement of OCD.In addition, because cognitive dysfunction also affects other aspects of OCD, the inventors conclude that improving cognitive dysfunction will additionally contribute to the overall improvement of OCD.

[0698] Improvement in OCD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0699] The improvement in OCD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in OCD in patients who also suffer from associated cognitive impairment, 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.

[0700] Patients with body dysmorphic disorder (BDD) have falsely perceived defects in their appearance that impair their ability to function in daily life and are accompanied by disturbing preoccupations, ritualistic behaviors, and emotional distress.

[0701] Patients with BDD may suffer from a treatment-resistant form of the disorder.

[0702] A variety of cognitive deficits have been identified in patients with BDD, including impaired memory, decision-making, and attentional fixation shifting, as well as cognitive interference and suppression of visual-spatial exploration.

[0703] Cognitive rehabilitation may be useful in addressing the cognitive deficits seen in people with BDD.

[0704] Cognitive impairment can be specifically assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) or the Montreal Cognitive Assessment (MoCA).

[0705] Functional magnetic resonance imaging of patients with BDD disorder reveals alterations within and / or between specific brain regions located in the default mode network, dorsal attention network, and salience network. These changes in functional connectivity suggest that maladaptive self-referential thinking may reflect an inability to regulate the balance between internal and external attention.

[0706] Treating patients suffering from BDD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of BDD.

[0707] The reduction or elimination of cognitive impairment in a patient with BDD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0708] The reduction or elimination of cognitive impairment in a patient 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.

[0709] The reduction or elimination of cognitive impairment in a patient with BDD is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0710] The reduction or elimination of cognitive impairment in a patient with BDD, 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 impairment, 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.

[0711] Reduction or elimination of cognitive impairment in a patient with BDD is reflected by an improvement in the Screen for Cognitive Impairment in Psychiatry (SCIP) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] The reduction or elimination of cognitive impairment in a patient with BDD, 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 impairment, 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.

[0713] As mentioned above, cognitive dysfunction is closely related to BDD.Therefore, improving cognitive dysfunction will also lead to the improvement of BDD.In addition, because cognitive dysfunction also affects other aspects of BDD, the inventors conclude that improving cognitive dysfunction will additionally contribute to the overall improvement of BDD.

[0714] Improvement in BDD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0715] The improvement in BDD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0716] Post-traumatic stress disorder (PTSD) Post-traumatic stress disorder (PTSD) is a mental health condition that can develop based on a terrifying event that a patient has experienced or witnessed. Symptoms include flashbacks, nightmares, and severe anxiety and uncontrollable thoughts about the event.

[0717] Patients with PTSD may suffer from a treatment-resistant form of the disorder.

[0718] Post-traumatic stress disorder (PTSD) is characterized by abnormal cognitive and emotional processes that interfere with daily life after a traumatic event. Abnormalities in the cognitive domains of memory, attention, problem-solving, and planning have been described as hallmarks of PTSD.

[0719] Cognitive theories of PTSD implicate the interplay between emotion and cognition in the development of PTSD symptoms and features. In particular, it is believed that an overemphasis on threat-seeking cognitive processes may explain why cognitive resources are allocated poorly to non-threat-related information, leading to attentional bias.

[0720] The severity of PTSD symptoms correlates with worsening cognitive performance, particularly with regard to psychomotor speed / attention and memory.

[0721] PTSD can be assessed using the Clinical Diagnostic Interview Scale for PTSD for DSM-5 (CAPS-5), a structured diagnostic questionnaire for PTSD that corresponds to the DSM-5 criteria for PTSD.

[0722] Cognitive impairment in PTSD can be assessed using the Montreal Cognitive Assessment (MoCA).

[0723] Analysis of resting-state functional magnetic resonance imaging in patients with PTSD reveals alterations within and / or between regions located in the default mode network and salience network.

[0724] Treating patients suffering from PTSD, including treatment-resistant forms of the disorder and associated cognitive impairment, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in amelioration of the PTSD.

[0725] The reduction or elimination of cognitive impairment in a patient suffering from PTSD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0726] The reduction or elimination of cognitive impairment in a patient suffering from 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.

[0727] The reduction or elimination of cognitive impairment in a patient suffering from PTSD is reflected by an improvement in the score on at least the Montreal Cognitive Assessment (MoCA) score about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0728] The reduction or elimination of cognitive impairment in a patient suffering from PTSD, 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 impairment, 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.

[0729] As mentioned above, cognitive dysfunction is closely related to PTSD.Therefore, improving cognitive dysfunction will also lead to the improvement of PTSD.In addition, because cognitive dysfunction also affects other aspects of PTSD, the inventors conclude that improving cognitive dysfunction will additionally contribute to the overall improvement of PTSD.

[0730] Improvement in PTSD in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0731] Improvement in PTSD in patients who also suffer from associated cognitive impairment, as reflected by a decrease in CGI-S score, occurs within 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 impairment, 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.

[0732] pain disorders Cognitive dysfunction occurs in patients suffering from pain and is associated with chronic pain.

[0733] Chronic pain, also called persistent pain, is long-term pain that persists beyond the normal recovery period, for example, after an injury or surgery, despite medication or treatment. Patients may also suffer from chronic pain without any apparent cause, such as a history of injury or surgery.

[0734] Chronic pain is associated with impaired cognitive function, which may be secondary to increased competition for cognitive resources. Cognitive impairment is most evident in the domains of attention, memory, executive function, and slowed processing speed. A bidirectional relationship exists between cognition and pain.

[0735] Cognitive function can be assessed objectively using subjective self-report measures or with formal, empirically validated neuropsychological tests that focus on one or more aspects of cognition.

[0736] A suitable test to assess cognitive impairment is the Montreal Cognitive Assessment (MoCA).

[0737] Chronic pain patients exhibit brain changes in brain function and structure. These changes are associated with pain that persists long after the initial nociception has resolved. Many brain regions and networks involved in pain processing are also involved in other sensory and especially cognitive tasks. Resting-state functional magnetic resonance imaging reveals alterations in distinct regions within and / or between the default mode network, the somatomotor / sensorimotor network, and the salience network.

[0738] Treating patients suffering from chronic pain and associated cognitive impairment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive impairment and results in improvement of the chronic pain.

[0739] The reduction or elimination of cognitive impairment in a patient suffering from chronic pain is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0740] The reduction or elimination of cognitive impairment in a patient 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.

[0741] The reduction or elimination of cognitive impairment in a patient suffering from chronic pain is reflected by an improvement in the Montreal Cognitive Assessment (MoCA) score at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0742] The reduction or elimination of cognitive impairment in a patient suffering from chronic pain, 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 impairment, 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.

[0743] As mentioned above, cognitive dysfunction is closely related to chronic pain.Therefore, the improvement of cognitive dysfunction will also lead to the improvement of chronic pain.In addition, because cognitive dysfunction also affects other aspects of chronic pain, the inventors conclude that the improvement of cognitive dysfunction will additionally contribute to the overall improvement of chronic pain.

[0744] Improvement in chronic pain in patients who also suffer from associated cognitive impairment, 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0745] The improvement in chronic pain in patients who also suffer from associated cognitive impairment, as reflected by a reduction in CGI-S score, occurs within 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 impairment, 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.

[0746] Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain throughout the body or multiple parts, 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 "fibrofog"), sensitivity to light, noise, smells, and temperature, or digestive problems such as abdominal bloating or constipation.

[0747] Research has shown that people with fibromyalgia have increased sensitivity to pain, causing them to feel pain that others do not.

[0748] Patients with fibromyalgia often report forgetfulness and cognitive decline, referred to as "fibrofog." "Fibrofog" is a subjectively experienced cognitive impairment associated with fibromyalgia. It includes loss of mental clarity and impaired attention and memory. The combination of pain, fatigue, poor sleep quality, and cognitive impairment often interferes with the ability to function at home and at work.

[0749] Previous treatments for fibromyalgia have been symptomatic.

[0750] Cognitive impairment in fibromyalgia can be assessed using the Montreal Cognitive Assessment (MoCA) or the Mini-Mental State Examination (MMSE).

[0751] Brain imaging studies and other investigations 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.

[0752] Resting-state functional magnetic resonance imaging in patients with fibromyalgia reveals 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.

[0753] Treatment of 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.

[0754] The reduction or elimination of cognitive impairment 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0755] The reduction or elimination of cognitive impairment 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.

[0756] The reduction or elimination of cognitive impairment in a patient suffering from fibromyalgia is reflected by an improvement in at least the Montreal Cognitive Assessment (MoCA) at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, 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.

[0757] The reduction or elimination of cognitive impairment in a patient suffering from fibromyalgia, as reflected by an improvement in the MoCA score, occu...

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.

2. The pharmaceutical composition according to claim 1, wherein the cognitive impairment is a defect or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual motor function, and social cognition.

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

4. The pharmaceutical composition according to claim 3, wherein the patient suffering from the aforementioned mental illness or 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 a depressive episode associated with the 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 suffers 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.

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 administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours, at least seven days, at least fourteen days, and / or at least twenty-eight days.

11. The pharmaceutical composition according to claim 3, wherein the treatment results in improvement of the diagnosed impairment 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 who also suffer from associated cognitive impairment, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, is observed about two hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours, at least seven days, at least fourteen days, and / or at least twenty-eight days.

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

14. 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.

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

16. The pharmaceutical composition according to claim 15, wherein a larger dose of the drug is used in each of the subsequent doses than in the previous dose.

17. The pharmaceutical composition according to claim 15, wherein the patient receives a subsequent dose unless the patient experiences a hallucinogenic peak experience.

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

19. The pharmaceutical composition according to claim 18, wherein the patient receives a second or third dose unless the patient has already experienced a hallucinatory peak experience.

20. The pharmaceutical composition according to claim 1, wherein a first dose of 5-MeO-DMT is approximately 6 mg, a second dose of 5-MeO-DMT is approximately 12 mg, a third dose of 5-MeO-DMT is approximately 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered.

21. The pharmaceutical composition according to claim 20, wherein the patient receives a second or third dose unless the patient has experienced a hallucinogenic peak experience.

22. The pharmaceutical composition according to claim 21, wherein the interval between the two administrations is 1 hour or more and within 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

23. The manifestation of the hallucinatory peak experience is identified by achieving at least 60% of the maximum 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 score in the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving at least 75 of the total score on the Peak Experience Scale (PES), according to claim 17.

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

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

26. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered to the patient in a dose or dosage regimen sufficient to induce a hallucinogenic peak experience.