Treating Anxiety

Abstract

In the treatment of patients suffering from anxiety, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used.

Description

[Technical Field]

[0001] The present invention relates to improved methods for treating anxiety, which occurs in patients suffering from anxiety disorders, but is also a symptom of other psychiatric or nervous system disorders.

[0002] Treatment involves administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Anxiety is a feeling of confusion and worry. Experiencing anxiety from time to time is a common part of life.

[0004] However, individuals with anxiety disorders often have intense, excessive, and persistent worries and fears about everyday situations.

[0005] Anxiety disorders are often accompanied by sudden, recurring feelings of intense apprehension and fear or dread (panic attacks) that peak within minutes.

[0006] These feelings of anxiety and panic may interfere with daily activities, be difficult to control, be disproportionate to the actual danger, and persist for long periods of time. Avoidance behaviors may result in an attempt to prevent these feelings.

[0007] Anxiety can be idiopathic or can occur in association with medical conditions such as psychiatric or nervous system disorders.In fact, some psychiatric and nervous system disorders are known to be associated with anxiety.Anxiety can also occur in patients suffering from certain medical conditions that lead to related psychiatric or nervous system conditions.

[0008] Anxiety can not only seriously affect quality of life, but can also lead to or exacerbate other mental and physical conditions, such as depression or other mental health disorders that may be associated with anxiety, cognitive dysfunction, sleep disorders (e.g., insomnia), substance abuse, digestive or bowel problems, headaches and chronic pain, social isolation, problems functioning in daily life, and suicide.

[0009] Current treatment options for conditions associated with anxiety are limited.

[0010] Thus, there is a need for improved treatments for anxiety associated with such conditions, particularly psychiatric or nervous system disorders in patients suffering from certain medical conditions that lead to associated psychiatric or nervous system conditions. Summary of the Invention

[0011] 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).

[0012] It is a further object of the present invention to provide improved psychoactive therapeutic compounds and dosage regimens therefor 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 therefor that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens therefor that are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. A further object of the present invention is to identify specific disease states and specific subgroups of disease states that would benefit from such improved psychoactive therapies.

[0013] 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 anxiety. The patient may be suffering from anxiety, a psychiatric or nervous system disorder and subthreshold anxiety, or may have a comorbidity of anxiety and an additional diagnosed disorder.

[0014] Anxiety may refer to psychiatric or nervous system disorders, for example disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication induced anxiety disorders, somatic symptom disorders, obsessive-compulsive and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD), post-traumatic stress disorder (PTSD), pain disorders, such as chronic pain, fibromyalgia and migraine, mental and behavioral disorders due to the use of psychoactive substances. , for example, in patients suffering from substance use disorders (SUDs), psychotic disorders such as schizophrenia, Parkinson's disease, dementia such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia, eating disorders, attention deficit hyperactivity disorder (ADHD), personality disorders such as schizotypal personality disorder and borderline personality disorder, autism spectrum disorder, chronic fatigue syndrome, or a medical health condition leading to a related mental or nervous system condition, for example, anxiety due to traumatic brain injury (TBI), HIV infection, or post-COVID symptoms.

[0015] Patients may also suffer from sleep disorders associated with anxiety.

[0016] The present invention also provides useful dose ranges and administration regimens for treating anxiety. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming that an equimolar amount is used.

[0018] As used in the context of the present invention, a "patient" to be treated is a human subject who has been diagnosed with anxiety by a licensed professional in accordance with licensed medical practice, or who has been diagnosed with an anxiety-related psychiatric or nervous system disorder by a licensed professional in accordance with licensed medical practice, in which case assessing anxiety may or may not be part of the diagnosis.

[0019] A diagnosis of a mental or nervous system disorder may be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. The diagnosis is made by a physician or psychologist. It is not sufficient for the human subject to consider themselves to be suffering from the disorder.

[0020] 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.

[0021] "Treatment of anxiety" is intended to include the management and care of a patient for the purpose of managing anxiety, and includes the administration of compounds and methods according to the present invention to reduce the signs and / or symptoms of anxiety or eliminate anxiety.

[0022] The patient may suffer from an anxiety disorder or anxiety-related disorder. The anxiety may be associated with a sleep disorder.

[0023] 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, and in this case, 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 have been carried out, particularly in the current episode of the disease, for example, in the current episode of depression, if the patient suffers from a disorder characterized by depressive episodes.

[0024] As used in the context of the present invention, "suicidal ideation" refers to thinking, considering, or planning about suicide. The presence of suicidal ideation in a patient is diagnosed by a physician or psychologist using established protocols and methods for diagnosing suicidal tendencies. Generally, it is not enough for a patient to believe that they are suffering from suicidal ideation. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of committing suicide or to have an "intent to act."

[0025] As used in the context of the present invention, unless otherwise indicated, 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 desired by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0026] "Clinical response" includes, but is not limited to, improvements on rating scales that assess (i) anxiety or aspects of anxiety and / or (ii) a psychiatric or nervous system disorder or aspects of such a disorder.

[0027] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, which is a measure of symptom severity, treatment response, and effectiveness of treatment.

[0028] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the opinion of the clinician (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0029] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in your patient?" This is rated on a 7-point scale: 1 = normal (no illness), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = patient with very severe illness.

[0030] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0031] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), a similarly brief format. After treatment, clinicians compare the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of project entry (before medication was started), this patient's condition has improved significantly since the start of treatment: 1 = very significantly; 2 = very significantly; 3 = very slightly; 4 = no change from baseline (before treatment was started); 5 = very slightly; 6 = very significantly; 7 = very significantly; since treatment was started."

[0032] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0033] Individual items and subcombinations of individual items of the scales described herein can be used to assess specific disease aspects.

[0034] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a possible predetermined amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered by inhalation, nasally, bucally, or sublingually.

[0035] As used in the context of the present invention, unless otherwise specified, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosing regimen") shall mean a defined sequence of one or more individual administrations.

[0036] 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 a sample divided by the amount of 5-MeO-DMT + 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 sample of 5-MeO-DMT (or a pharmaceutically acceptable salt thereof). The impurities may be contained in the starting material prior to aerosol formation or may be decomposition products.

[0037] 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%.

[0038] 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 density" 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.

[0039] anxiety Anxiety may be defined as "an anxious anticipation of future danger or misfortune accompanied by physical symptoms of discomfort or tension."

[0040] Anxiety is characterized simply by intense, excessive, persistent worry and fear about situations that are subjectively perceived as threatening, and is often accompanied by muscle tension, restlessness, fatigue, loss of ability to breathe, abdominal tightness, nausea, and difficulty concentrating.

[0041] In anxiety disorders, or other anxiety-related psychiatric or neurological disorders, feelings of anxiety are difficult to control and interfere with daily activities.

[0042] Anxiety is a central feature of anxiety disorders, including separation anxiety disorder, specific phobia, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance / medication-induced anxiety disorder.

[0043] Anxiety is also associated with several other psychiatric and nervous system disorders. Anxiety is also associated with sleep disorders.

[0044] Anxiety assessment Several rating scales for assessing anxiety are known in the art, and anxiety symptoms are further assessed as part of various rating scales used to assess psychiatric and nervous system disorders.

[0045] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. This scale is administered by a clinician. It has 14 items that can be divided into a group of psychological items (items 1-6 and 14) that specifically assess mental agitation and psychological distress, and a group of physical items (items 7-13) that specifically assess somatic complaints related to anxiety.

[0046] The HAM-A items are shown in the table below. [Table 1]

[0047] A total score is obtained by summing the 14 items. The total score ranges from 0 to 56. Higher scores indicate greater anxiety.

[0048] A score of ≦7 is considered to represent no or minimal anxiety; mild anxiety a score of 8-14; moderate anxiety a score of 15-23; and severe anxiety a score of ≧24.

[0049] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on physical symptoms. These items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (severe: barely tolerable). Total scores range from 0 to 63.

[0050] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0051] Scales for assessing mental and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders. Such scales are based on tests that can be self-administered or administered by a clinician.

[0052] Measures that may be used in accordance with the present invention include those known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0053] Treatment outcome is assessed using one or more indexes or scales at one or more time points after the course of treatment has ended.

[0054] Assessments can be performed after the acute psychedelic experience has subsided. An appropriate 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.

[0055] However, assessment of the effect on sleep disturbances could be performed as early as the day after treatment (i.e., day 1), allowing treated patients the opportunity to get at least one night's sleep.

[0056] Thus, evaluation on day 1 or evaluation on day 1 means evaluation on the day after dosing. Evaluation will be performed no later than 12 hours after the last dose, and in any event no later than one night after the last dose and no later than 36 hours after the last dose. Evaluation can be performed after about 24 hours.

[0057] Assessment on day 7 or assessment at day 7 refers to assessment on day 7 after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0058] Based on the endpoint that is established with a longer recall period (for example, MADRS is usually 7 days), when the clinical response is evaluated at an earlier time point (for example, 2 hours) after drug administration, for example, using one of the scales for assessing the severity of psychiatric or nervous system disorders, such endpoint can be reasonably modified (for example, the recall period 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 applied herein, unless recall period is specifically indicated.

[0059] At earlier 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.

[0060] 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 adapted recall periods as needed, so that any pre-treatment scores do not need to be carried forward.

[0061] The Brief Psychiatric Rating Scale (BPRS) is intended to screen for psychiatric symptoms in a structured manner. It is one of the most widely used scales for assessing psychiatric symptoms and was first published in 1962. Its design has since been updated. The version most commonly used today includes 18 different domains for evaluation by a physician or psychologist (Overall, J.E. and Gorham, D.R., 1962. The brief psychiatric rating scale. Psychological Reports 10, p. 799; Overall, J.E. and Gorham, D.R., 1988. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacology Bulletin 22, p. 97).

[0062] Eighteen items (hypochondriasis, anxiety, emotional withdrawal, conceptual integration disorder, guilt, tension, pedantic and unnatural postures, grandiosity, depressed mood, hostility, suspiciousness, hallucinated behavior, hypokinesia, uncooperativeness, unnatural thought content, flat affect, agitation, and disorientation) are scored, and each item is rated on a scale of 1 to 7.

[0063] The doctor or psychologist completes two tasks during the approximately 15-minute interview with the patient: • Ask the patient a series of questions from the list. • Check to see if the patient exhibits certain behaviors.

[0064] Based on the responses and observed behaviors, the physician or psychologist completes the BPRS form, ranking the severity of each area on a scale of 1 to 7. A score of 1 means no signs or symptoms, and a maximum score of 7 means signs or symptoms are present and severe. If a specific sign or symptom cannot be assessed, a score of 0 or "not assessed" is recorded.

[0065] The Columbia-Suicide Severity Rating Scale (C-SSRS) is a detailed questionnaire that assesses both suicidal behavior and suicidal ideation, helping to identify the immediate need for medical intervention and providing data for the overall evaluation of the effectiveness of treatment for suicidality. The C-SSRS is evidence-based and is part of national and international public health initiatives that involve the assessment of suicidality (Posner, K., Brown, GK, Stanley, B., Brent, DA, Yershova, KV, Oquendo, MA, Currier, GW, Melvin, GA, Greenhill, L., Shen, S., and Mann, JJ, 2011. The Columbia-Suicide Severity Rating Scale: Initial Validity and Internal Consistency Findings From Three Multisite Studies With Adolescents and Adults. American Journal of Psychiatry 168(12), pp. 1266-77).

[0066] The underlying mechanisms of anxiety Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0067] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0068] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0069] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0070] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0071] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks have been found to be impaired in various disease states, including certain forms of anxiety, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0072] Based on such studies, multiple brain regions have been linked to anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormalities in the connectivity between the amygdala-frontal region and the frontal-striatal region. Anxiety and anxiety disorders are associated with specific alterations in the resting-state network.

[0073] Anxiety and anxiety disorders exhibit abnormalities within and / or between the default mode network, salience network, and sensorimotor network. The resting balance within and / or between each of these networks differs in anxiety disorders.

[0074] Active Agent These considerations indicate that anxiety therefore poses a significant disease burden and deserves appropriate treatment.

[0075] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of anxiety and improve the condition overall.

[0076] One group of hallucinogens involves 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, collapse of self-boundaries, or even near-death experiences), while other effects such as sedation, narcosis, or hyperstimulation are minimal.

[0077] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines (the indoleamines are divided into two subsets, ergolines and tryptamines), the latter being derived from tryptamine.

[0078] 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.

[0079] Recently published clinical trials 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.

[0080] 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 that subsequently resolved, but a typical manic episode of psychotic proportions followed approximately 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after ingesting psilocybin mushrooms (self-reported). 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 classic hallucinogens.

[0085] As further detailed in the Examples section below, the inhibition constants (Ki values) 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 brains are 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity for 5-HT1A receptors, while psilocin and DMT exhibit moderate affinity. The inhibition constants (Ki values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains are 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for 5-HT2A receptors, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0086] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor and acts as a potent agonist. In the case of psilocin and DMT, the contribution of 5-HT2A binding is increased compared to 5-MeO-DMT, with the latter showing the largest difference in affinity for 5-HT1A compared to 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than 5-HT2A binding for the other two compounds.

[0087] 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, 5-HT1A agonists have anxiolytic effects. Furthermore, the dopamine system has been implicated in contributing to mania, with increased dopamine activity associated with mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0088] 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, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0089] 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).

[0090] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0091] 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.

[0092] 5-MeO-DMT can induce a peak experience (i.e., an experience characterized by an emotional perspective shift described as "loss of self") that often leads to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also exhibits a short duration of acute psychedelic 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 that may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0093] 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, as a radioligand, 3 Estimate nonspecific binding using [H]LSD, and serotonin, and K i was determined to be 2.3 nM.

[0094] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0095] 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.

[0096] 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.

[0097] 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. Resting-state functional connectivity analysis in patients with sleep disorders revealed modulation of functional connectivity between the SNU and regions within the default mode network.

[0098] 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.

[0099] 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.

[0100] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 and 5-HT1A receptors, as two mediators of its effects, including "resetting" functional network connectivity and neuroplasticity effects, 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.

[0101] Another characteristic of 5-MeO-DMT is its short half-life.

[0102] 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.

[0103] 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.

[0104] 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, therefore, does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0105] The properties of 5-MeO-DMT make the compound particularly suitable for treating anxiety 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 disorder.

[0106] As discussed in more detail below, the properties of 5-MeO-DMT also allow for specific dosing regimens.

[0107] 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.

[0108] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0109] 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.

[0110] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0111] 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.

[0112] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced into one or more hydrogen positions of the N-linked methyl group. Yet another example includes forms of 5-MeO-DMT 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.

[0113] Methods for preparing these compounds are known in the art.

[0114] 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, and mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0115] 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.

[0116] 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.

[0117] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0118] 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.

[0119] 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 4is defined as above.

[0120] Prodrugs (particularly those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0121] 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).

[0122] Methods for preparing the prodrugs discussed herein are known in the art.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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 formulation of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0127] Buccal or sublingual administration may also rely on a pharmaceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in the form of a formulation (e.g., tablet, film, spray, cream) as commonly known in the art.

[0128] Administration is particularly 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 density of the aerosol is about 0.5 mg / L to about 18 mg / L, for example, 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.

[0129] The aerosol particles preferably contain less than 1 wt. % impurities, particularly less than 0.5 wt. % impurities, and further preferably contain 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.

[0130] 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.

[0131] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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 rate of about 12 1 / min for about 15 seconds.

[0136] The aerosol particles can be contained in a volume of about 3 liters or less, particularly about 1 to about 3 liters, for example, about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0137] 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 density so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0138] Aerosols 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 used for aerosolization (e.g., crystalline form or thin layer form); c) the amount of thermal energy to which the compound is exposed (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).

[0139] 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, preferably nearly completely or completely, to a defined extent; 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 the aerosol can be inhaled by a patient in a single inhalation (i.e., in 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.

[0140] 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.

[0141] 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) is capable of being delivered to a patient by a single inhalation.

[0142] 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 drug degradation products by aerosol volume and which can be delivered to a patient by a single inhalation, is achieved by specifying a) the dose 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).

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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. Effective specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0147] 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).

[0148] 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 (about 400 per meter).

[0149] Several different materials are used to construct solid supports. Such material types include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of material types: 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.

[0150] 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 2 1 / g (>1000 psi) alumina (Aldrich, St. Louis, Mo.) and silicon wafers such as those used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0151] 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 may range from about 0.1 μm to about 10 μm, particularly from 0.3 μm to 7.5 μm.

[0152] Preferably, the total volume of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of about 6 liters per minute to about 40 liters per minute, preferably about 8 liters per minute to about 16 liters per minute, and the duration of the airflow is selected so that the total aerosol volume does not exceed about 3 liters, preferably about 1 liter to 3 liters, e.g., 2 liters to 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 of the airflow 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 of the airflow 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 of the airflow 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.

[0153] The aerosol generation rate is greater than 0.1 mg / sec.

[0154] The aerosol particle mass density of the aerosol is about 0.5 mg / l to about 18 mg / l, for example, 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.

[0155] 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.

[0156] 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.

[0157] 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 5-MeO-DMT degradation products; and 3) is capable of being delivered to a patient by a single inhalation.

[0158] 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.

[0159] Dosing regimen The present invention also provides dose ranges, specific doses, and administration regimens (administration schemes).

[0160] The present invention is based in part on the inventors' conclusion that the acute onset of a peak psychedelic experience following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, may causally facilitate therapeutic efficacy in patients suffering from anxiety, or at least serve as a surrogate behavioral marker of an underlying unknown therapeutic mechanism.

[0161] Thus, achieving peak experience more quickly, 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.

[0162] 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 psychedelic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily), which are 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 could otherwise result in physical side effects, such as serotonin syndrome, negative psychological reactions, such as flashbacks of the experience at a later time, the induction of mania or hypomania, or a less meaningful psychedelic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, starting with a low dose generally allows patients to become accustomed to the psychedelic experience and prepare them for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at those higher doses. Additionally, the prospect of initiating treatment at lower doses will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0163] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate and modulate the reproducibility of peak experiences, 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 psychedelic effects, and the rapid development of tolerance (i.e., waning or disappearance of psychedelic effects after re-administration), which may last for several days.

[0164] Patients, as defined herein, suffering from anxiety are treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0165] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for anxiety).

[0166] The dosage of 5-MeO-DMT defined herein and administered to a patient suffering from anxiety is within the range of about 1 mg to about 25 mg, or any amount within this range, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific amounts that are effective 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. 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 given 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).

[0167] In a preferred embodiment, the improved method for treating a patient suffering from anxiety as defined herein with a therapeutically effective amount of 5-MeO-DMT comprises the occurrence of a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0168] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from anxiety with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, including a clinical response that occurs 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.

[0169] In a preferred embodiment, the improved method for treating a patient, as defined herein, suffering from anxiety with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0170] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 doses, with 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.

[0171] 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, with 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.

[0172] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 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.

[0173] In one embodiment, the dose 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.

[0174] In a preferred embodiment, the dose 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.

[0175] In an even more preferred embodiment, the dose 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 peak psychedelic experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0176] For embodiments in which the dose is increased with each subsequent administration, the dose 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 dose of the previous administration. For example, if the dose of the first administration is 6 mg and the dose increment is 6 mg, the dose of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dose of the third administration will be 18 mg.

[0177] In a preferred embodiment, the dose 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 dose, and then increased to a dose selected from about 8 mg to about 14 mg for the second dose and to a dose selected from about 14 mg to about 20 mg for the third dose, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third doses are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0178] In a further preferred embodiment, the dose 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 peak psychedelic experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dose in that first treatment block being used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a peak psychedelic experience at a dose of 18 mg, and therefore the highest dose in the first treatment block was 18 mg, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0179] In a most preferred embodiment, the dose 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, then increased to a dose selected from about 8 mg to about 14 mg for the second administration of the first treatment block, and to a dose selected from about 14 mg to about 20 mg for the third administration of the first treatment block, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects, with the highest dose in that first treatment block being used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0180] 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.

[0181] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0182] The onset of a "peak psychedelic experience" in a patient can be identified by the achievement of at least 60% of the maximum possible score on each of the four subscales (sacredness, positive mood, transcendence of time and space, and indescribable) of the 30-item Mystical Experiences Questionnaire-Revised (MEQ-30) (reviewed in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0183] The onset of a "peak psychedelic experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (reviewed in Roseman L et al., Front Pharmacol. 2018;8:974).

[0184] 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 referred to as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, scored on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How lost was your control? 3. How profound (i.e., profound and significant) was the experience?

[0185] Treating Anxiety According to the present invention, anxiety occurring in patients suffering from anxiety disorders or other anxiety-related psychiatric or nervous system disorders can be treated. Additionally, anxiety occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0186] In patients suffering from anxiety associated with another psychiatric or nervous system disorder or sleep disorder, eg, insomnia, treatment of anxiety according to the present invention improves the anxiety-related condition.

[0187] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0188] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0189] Thus, in accordance with the present invention, by affecting these networks with the treatments described herein, anxiety will be improved. If the treated patient suffers from another psychiatric or nervous system disorder related to anxiety, that disorder will also be improved, and if the treated patient suffers from a sleep disorder, e.g., insomnia, that sleep disorder, e.g., insomnia, will also be improved.

[0190] To further support the clinical application of 5-MeO-DMT in patients suffering from anxiety, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric reasons, noting the specific improvement in anxiety that is also commonly seen in patients with other disorders.

[0191] 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 condition, the inventors have determined that certain clinical findings from the trial are relevant to devising treatments for anxiety and other anxiety-related conditions, as discussed in more detail below.

[0192] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are those receiving a single 12 mg dose and those receiving an individualized daily dose regimen (IDR) that allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported psychedelic experience.

[0193] Data collected included assessments of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various scales, noting that items related to anxiety, as well as items in specific subscores, are related to other conditions based on similarly altered functional connectivity within and / or between resting-state networks.

[0194] Several patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0195] Furthermore, a particular condition that can be treated by administration of 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to a patient to reduce or eliminate anxiety in the patient.

[0196] In this regard, a BPRS item of particular relevance is "Anxiety." This item concerns reported apprehension, tension, fear, panic, or worry. Possible scores are as follows: 1- No anxiety. 2 - Very mild. Reports some discomfort due to worries that occur more often or infrequently than is normal for most healthy people. 3 - Mild. Frequent worry, but able to quickly shift attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily focus on other things, but does not impair functioning, or occasional autonomic anxiety, but does not impair functioning. 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety, or some areas of functioning are impaired by anxiety or worry. 6 - Severe. Autonomic anxiety occurs daily but not all day long, or many areas of functioning are impaired by anxiety or constant worry. 7 - Severe. Autonomic anxiety is present and persists throughout the day, or most areas of functioning are impaired by anxiety or constant worry.

[0197] The aggregated BPRS "anxiety" item score across all eight patients in the study group receiving the individualized dosing regimen was 37 at baseline.

[0198] After 3 hours, the score decreased to 19, which corresponds to an 18-point or 49% improvement. One day after treatment, the score decreased to 16, which corresponds to a 21-point or 57% improvement. Seven days after treatment, the score decreased to 17, which corresponds to a 20-point or 54% improvement.

[0199] Aggregate BPRS "anxiety" item scores across all four patients in the 12 mg group had a baseline of 25.

[0200] After 3 hours, the score decreased to 11, which corresponds to a 14-point or 56% improvement. On day 1 after treatment, the score decreased to 6, which corresponds to a 19-point or 76% improvement. On day 7 after treatment, the score decreased to 6, which corresponds to a 19-point or 76% improvement.

[0201] The inventors conclude that 5-MeO-DMT may be used to treat anxiety in patients, such as those suffering from anxiety disorders and those suffering from psychiatric or nervous system disorders with associated anxiety.

[0202] Thus, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0203] The MADRS item "Inner tension" describes increased mental tension toward unexplained discomfort, restlessness, inner agitation, panic, fear, or distress, rated according to intensity, frequency, duration, and the degree of relief sought.

[0204] If the patient is calm and experiences only fleeting inner tension, a score of 0 is assigned. If there is occasional agitation and unexplained discomfort, a score of 2 is assigned. If there is continuous inner tension or intermittent panic that the patient manages to overcome with some difficulty, a score of 4 is assigned. If there is constant fear or distress and overwhelming panic, a score of 6 is assigned.

[0205] In the above study of patients with TRD, the aggregated MADRS "internal tension" item score across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 26. After two hours, the score decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, the score decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, the score decreased to 12, corresponding to a 14-point or 54% improvement.

[0206] Aggregate scores for the MADRS "internal tension" item across all four patients in the 12 mg group showed a baseline of 13. After two hours, the score had decreased to 2, corresponding to an 11-point or 85% improvement. On post-treatment day 1, the score had decreased to 3, corresponding to a 10-point or 77% improvement. On post-treatment day 7, the score had decreased to 5, corresponding to an 8-point or 62% improvement.

[0207] These results further support the inventor's conclusion that treatment according to the present invention reduces or eliminates symptoms of anxiety.

[0208] Treatment according to the present invention results in a clinical response in patients suffering from anxiety symptoms reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0209] The clinical response reflected by at least a 50% reduction in the HAM-A score in a patient suffering from anxiety compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response reflected by at least a 50% reduction in the HAM-A score in a patient suffering from anxiety preferably persists for at least 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.

[0210] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms is reflected by a HAM-A score of 7 or less about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0211] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, preferably persists for at least 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.

[0212] Thus, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0213] Anxiety and sleep A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder, or a medical health condition that leads to a related psychiatric or nervous system condition. Sleep disorders affect a person's ability to function properly while awake, and in particular impair cognitive function and cause anxiety.

[0214] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. NREM sleep can be divided into four stages (I-IV). These NREM stages correspond to increasing depths of sleep. NREM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, NREM sleep is deeper and occupies a disproportionate amount of time, especially within the first sleep cycle. As the night progresses, NREM sleep becomes shallower, with a greater proportion of each cycle allocated to REM sleep.

[0215] Normal, healthy sleep consists of different stages, as outlined above, which proceed sequentially and in a tightly regulated sequence throughout the night.

[0216] Disruption of this tight regulation results in sleep disorders.

[0217] Common forms of sleep disorders include disorders of sleep initiation and maintenance (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or incomplete awakening (parasomnia), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0218] Insomnia is a sleep disorder that makes it difficult for people to fall asleep or stay asleep. People with insomnia have difficulty falling asleep, frequent awakenings during the night, difficulty returning to sleep, waking too early in the morning, unrefreshing sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, concentration problems, or accidents at work or while driving.

[0219] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. Sleep drunkenness involves difficulty transitioning from sleep to wakefulness. Individuals experiencing sleep drunkenness report waking up with confusion, disorientation, and sluggishness, followed by repeated returns to sleep.

[0220] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances resulting from alterations in an individual's internal circadian rhythm or from imbalances between the circadian rhythm and desired or necessary work or social schedules. This dyssynchronization can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep duration is typically shortened and disrupted, performance during desired wakefulness is reduced, and intermittent opportunities to return to a normal sleep schedule are unsuccessful.

[0221] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) that people experience before falling asleep, during sleep, or during periods of wakefulness between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0222] Sleep-related breathing disorders are characterized by abnormal breathing difficulties during sleep. Breathing is a complex process that depends heavily on the coordinated action of respiratory muscles and the brain (control center). One form of sleep-related breathing disorder is central sleep apnea. Central sleep apnea occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea potentially has serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation due to microarousals or awakenings. The result can be excessive daytime sleepiness.

[0223] In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0224] Not getting adequate amount or quality of sleep can lead to personality changes and may exacerbate existing mental disorders or even precipitate the onset of new ones.

[0225] Sleep disorders such as insomnia are often comorbid with anxiety. Insomnia often precedes the onset of anxiety, so insomnia and anxiety may be mutually influential conditions, while anxiety symptoms are associated with abnormal sleep-wake cycles and can therefore lead to sleep disorders. For example, excessive worry and fear can make it difficult to fall asleep and stay asleep throughout the night.

[0226] Anxiety affects the sleep cycle because anxiety and pre-sleep rumination affect rapid eye movement (REM) sleep, which involves the most vivid dreaming. Sleep is more likely to be disrupted because it often induces more disturbing dreams.

[0227] Furthermore, the difficulty of falling asleep itself can create sleep anxiety, which compounds the problem and reinforces a person's fears and obsessions. These negative thoughts about going to bed, a form of anticipatory anxiety, can make a healthy sleep schedule and routine difficult.

[0228] Poor sleep can exacerbate anxiety and contribute to the vicious cycle of insomnia and anxiety.

[0229] Dysfunction of the locus coeruleus norepinephrine system (LC-NS), a brainstem region important for arousal and attention, has been implicated in insomnia and is associated with anxiety symptoms in patients with chronic insomnia.

[0230] Poor sleep has a significant impact on functional impairment: patients suffering from anxiety and sleep disorders experience significantly reduced mental health-related quality of life and increased disability compared to patients with anxiety alone.

[0231] Sleep disturbances are very common in patients with social anxiety disorder, agoraphobia, phobias, and substance / medication-induced anxiety disorders, given the bidirectional relationship between sleep disorders (mainly insomnia) and anxiety.

[0232] Separation anxiety disorder is also associated with sleep disturbances, which are part of the diagnostic criteria for separation anxiety disorder. Sleep disturbances in patients with separation anxiety disorder include nightmares, difficulty falling asleep or staying asleep, early awakenings, and parasomnias.

[0233] In the case of generalized anxiety disorder, sleep disturbances, particularly those involving difficulty falling asleep or staying asleep, or restless, unsatisfactory sleep, are key features. Sleep disturbances are associated with significant impairment in GAD. In the DSM-5 criteria, sleep disturbance is one of six symptoms (at least three of which must be present over a period of time to meet the diagnosis of GAD).

[0234] Sleep disorders (especially insomnia and hypersomnia) are very common in patients with panic disorder. Individuals suffering from panic disorder may also experience nocturnal panic attacks, which are distinct from night terrors. Nocturnal panic attacks may occur without provocation and often result in difficulty falling asleep again.

[0235] Treatment for sleep disorders varies depending on the type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatments may also include medication or psychotherapy.

[0236] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve relevant therapeutic benefits.

[0237] 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.

[0238] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treatment of depression does not necessarily lead to improvement of the associated sleep disorders. Most antidepressants have been shown to affect sleep structure, and some classes of antidepressants improve sleep, while others may cause sleep disorders.

[0239] To assess sleep, parameters such as sleep time, sleep architecture, sleep latency, and frequency and duration of wakefulness throughout the night can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-report measures (questionnaires).

[0240] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic, where various functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0241] Another quantitative measurement is actigraphy, in which an actimetry sensor is worn to measure motor activity, which is continuously recorded and used to assess the sleep-wake cycle. This technology allows patients to continue their normal routine while the necessary data is recorded in a natural sleep environment.

[0242] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine the time it takes a person to fall asleep during multiple test naps. An average sleep latency of approximately 10 minutes is considered normal. Less than 8 minutes indicates a sleep disorder / excessive daytime sleepiness. Analysis of accompanying brain activity can aid in further diagnosis of sleep disorders.

[0243] Sleep assessment questionnaires capture assessment of elements of sleep quality such as perceived depth of sleep, difficulty waking, and feeling rested after sleep, in addition to other factors that may affect sleep quality such as comorbid conditions and medication use. Anxiety can be part of the assessment because anxiety and sleep disorders are related.

[0244] Assessment of qualitative aspects of the sleep experience is important because sleep disorders can often persist despite normal quantitative measures of sleep.

[0245] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful for tracking patient progress. Self-administered sleep questionnaires completed by patients are therefore an important mainstay of the assessment of sleep disorders in clinical practice.

[0246] Various sleep quality indices are known. The following indices each include examples of questionnaires for assessing sleep generally, and for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias specifically. However, the present invention is not limited to the use of any particular index or questionnaire.

[0247] Some questionnaires rely on a recall period (recall window) of several days or weeks. While this may be appropriate for diagnosing sleep disorders, it is not always appropriate for assessing therapeutic efficacy, especially the rapid onset of post-treatment effects. For some questionnaires, the recall window can be modified so that the scores obtained reflect the post-treatment period. To assess the effects of treatment on the sleep of patients suffering from certain conditions, the questionnaires specifically considered herein rely on a recall window that begins no earlier than the time when the acute psychedelic experience has subsided after the last administration. To meet this criterion, the normally applied recall window is modified as necessary.

[0248] Sleep quality can generally be assessed, for example, with the Sleep Quality Scale (SQS) and the Sleep-50 Questionnaire.

[0249] The Sleep Quality Scale (SQS) is a comprehensive assessment tool designed to achieve a general and efficient measure suitable for assessing sleep quality in various patient and research populations. Individual questions about daytime symptoms, such as attention, concentration, and memory problems (item 15, "Lack of sleep makes it hard to think," item 19, "Lack of sleep makes me make mistakes at work," item 21, "Lack of sleep makes me forget things easily," and item 22, "Lack of sleep makes it hard to concentrate at work"), recovery after sleep, problems initiating and maintaining sleep, difficulty waking, and sleep satisfaction can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more acute sleep disturbances (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). Respondents are asked to report their experiences during the previous month or another appropriate recall period.

[0250] Successful treatment is indicated by a decrease in score.

[0251] The Sleep-50 questionnaire consists of 50 items designed to screen for various types of sleep disorders in the population. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and conditions, as well as diagnostic factors such as sleep apnea, insomnia, narcolepsy, restless legs / periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep disorders on daily functioning. For each item, respondents are provided with a scale from 1 ("not at all") to 4 ("very often") and asked to indicate the extent to which the item matches their experience over the previous month or another appropriate recall period.

[0252] For a diagnosis of a sleep disorder, not only must certain subscales (e.g., insomnia) exceed certain cutoff points, but respondents must also meet a cutoff of at least 3 or 4 ("quite often" or "very often," respectively) on subscales assessing the impact of sleep disorders on daily functioning (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0253] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0254] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other instruments include the Insomnia Severity Index, the Espie Sleep Disorders Questionnaire, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0255] 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.

[0256] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) habitual sleep efficiency, (5) sleep disturbances, (6) use of sleep medications, and (7) daytime dysfunction.

[0257] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Detailed scoring instructions for the Pittsburgh Sleep Quality 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.

[0258] 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. A cutoff score of 5 for the overall score distinguishes between those 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.

[0259] 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.

[0260] The Insomnia Severity Inventory (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective satisfaction with sleep, and the extent to which insomnia interferes with daily functioning (item 3, "To what extent do you think your sleep disturbances interfere with daily functioning (e.g., daytime fatigue, ability to function at work / daily chores, concentration, memory, mood, etc.)?"), the extent to which the respondent perceives their insomnia as more significant than others, and the overall level of distress caused by the sleep disturbance). Individual responses can be scored from 0 (= none) to 4 (= very much). Higher total scores correspond to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 means "subthreshold insomnia," 15–21 means "clinical insomnia (moderate severity)," and 22–28 means "clinical insomnia (severe)" (A. Shahid et al., loc.cit.). The typical recall period for an ISI is two weeks, although other suitable recall periods may be used herein.

[0261] Successful treatment is indicated by (i) a reduction in score, for example >7 points, especially >8 points, and preferably (ii) a reduction below the cut-off for clinically significant insomnia.

[0262] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. Following assessments of restlessness / irritability, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ specifically addresses thoughts about the causes of sleep problems. Respondents use a 5-point scale to indicate how frequently specific statements about insomnia describe their experience, with 1 meaning "never true" and 5 meaning "true most of the time." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc.cit.;).

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

[0264] The Patient-Reported Outcomes Information System (PROMIS®) Sleep Disorders Instrument is a universal scale for assessing sleep disorders. This instrument is available as a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulties related to getting and staying asleep over a 7-day period.

[0265] Each item on the measure is rated on a 5-point scale. The item raw scores are summed to obtain a total raw score. The total raw score is then converted to a standardized T-score using a conversion table.

[0266] Successful treatment is indicated by a decrease in the T-score.

[0267] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0268] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stalled in traffic. Using a scale of 0 to 3 (0 meaning "I will never fall asleep" and 3 meaning "I will likely doze off"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., loc.cit.).

[0269] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0270] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific point in time. This single-item scale requires respondents to select one of seven statements that best describes their perceived current level of sleepiness. Levels of sleepiness are assessed using a scale ranging from 1 (= active, lively, alert, fully awake) to 7 (= almost drowsy, sleep onset occurs quickly, unable to maintain wakefulness) (A. Shahid et al., loc.cit.).

[0271] Successful treatment is indicated by a decrease in score.

[0272] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0273] 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).

[0274] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0275] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc.cit.). An appropriate recall period may also be selected.

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

[0277] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Scale. The 10-item questionnaire asks respondents to indicate how acutely affected they have been by the disorder over the past week using a Likert-type rating. Questions can be categorized into one of two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep problems, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their experience with RLS on a scale of 0 to 4 (4 representing the most severe and frequent symptoms, 0 representing the least). Total scores can range from 0 to 40. As a brief measure with good psychometric quality, this instrument may be appropriate for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes. (A. Shahid et al., loc.cit.)

[0278] Treatment response can be assessed by a reduction in score.

[0279] Treatment response can be assessed by the use of quantitative measurements such as polysomnography or actigraphy and / or questionnaires as described above. Depending on the sleep scale, a significant decrease or increase in the total score, or a significant decrease in the prevalence, frequency, and impact on daily functioning, respectively, indicates a treatment-induced improvement in the sleep disorder.

[0280] The severity of anxiety can be assessed using the 14-item Hamilton Anxiety Scale (HAM-A), in which assessment of sleep disturbances is an integral part of the scale. Item 4 is "insomnia," defined as "difficulty falling asleep, sleep interruptions, unsatisfying sleep, and fatigue upon awakening, dreams, nightmares, and night terrors." Each item is scored on a scale of 0 (absent) to 4 (severe).

[0281] Resting-state fMRI has been widely applied to patients with sleep disorders to improve understanding of the pathophysiology and potential compensatory mechanisms involved.

[0282] Alterations in the resting-state network can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders and sleep-related movement disorders.

[0283] In patients with insomnia, dysfunctional connectivity has been observed within the default mode network (DMN) and the salience network, which are involved in the detection and integration of emotional and sensory stimuli. Studies suggest 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 patients' insomnia, subjective distress, and poor sleep continuity.

[0284] For example, sleep deprivation in healthy subjects leads to altered functional connectivity within and / or between the default mode network, dorsal attention network, and salience network, and these alterations in brain functional connectivity bear some resemblance to vulnerability patterns in Alzheimer's disease patients.

[0285] The default mode network is affected in patients with hypersomnia: for example, in idiopathic hypersomnia, distinct DMN hubs, the precuneus and medial prefrontal cortex, show significant alterations, and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0286] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disturbances contribute to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as reactivity and alertness. Furthermore, the functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disturbances may result in alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various disorders associated with circadian rhythm disturbances.

[0287] Although it is technically difficult to perform functional brain imaging during a parasomnia event, precuneus differences have been observed in disturbances of arousal that represent non-REM parasomnia.

[0288] The precuneus is involved in analyzing and integrating visual, auditory, and sensory 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.

[0289] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, show significant global and local connectivity deficits, especially in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems.Sleep-related movement disorders, such as periodic limb movement disorder during sleep, are reflected by changes in the prefrontal motor control pathway, a subregion of the default mode network.In addition, activity in the cerebellum and thalamus can be observed, along with additional activation in the red nucleus and brainstem.

[0290] Resting-state networks involved in sleep regulation are often also involved in cognition, and thus, in accordance with the present invention, affecting those networks by treatment according to the present invention results in improvement of sleep disorders and, if the treated patient suffers from anxiety, also in improvement of anxiety.

[0291] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that administration of 5-MeO-DMT can successfully treat sleep disorders.

[0292] The TRD study, described in more detail in the Examples section below, assessed, among other things, the MADRS item "Decreased Sleep," which reflects insomnia.

[0293] The MADRS item "Decreased Sleep" refers to the experience of a decrease in the duration or depth of sleep compared to the subject's normal pattern when healthy. A score of 0 is assigned if the subject is able to sleep normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, light, or intermittent sleep. A score of 4 means at least 2 hours of reduced or interrupted sleep. A score of 6 means less than 2 or 3 hours of sleep.

[0294] Aggregate scores for the MADRS "Decreased Sleep" item across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 25. By day 1 of treatment (the earliest time point to assess the treatment's impact on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 of treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0295] The combined MADRS "Decreased Sleep" score across all four patients in the 12 mg group had a baseline of 12. After one day of treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. After seven days of treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0296] Thus, the score for the scale item "Decreased Sleep," which is particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat sleep disorders, particularly in patients suffering from psychiatric or nervous system disorders.

[0297] Treatment of patients suffering from sleep disorders, particularly insomnia, and associated anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the sleep disorder, particularly insomnia.

[0298] The reduction or elimination of anxiety in patients suffering from sleep disorders, particularly insomnia, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 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.

[0299] The reduction or elimination of anxiety 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.

[0300] As mentioned above, anxiety is an important aspect in patients suffering from sleep disorder.Therefore, the improvement of anxiety also leads to the improvement of sleep disorder.Because anxiety also affects other aspects of sleep disorder, the inventors conclude that the improvement of observed anxiety also contributes to the overall improvement of sleep disorder, especially insomnia.

[0301] In the case of idiopathic sleep disorders, a 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 1. Preferably, a decrease in the CGI-S score of at least 2 and / or a score of 0 is achieved. A decrease in the CGI-S score of at least 3 and / or a score of 0 is particularly preferred.

[0302] Improvement in idiopathic sleep disturbance, as reflected by a decrease in CGI-S score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0303] Improvement in idiopathic sleep disturbance, 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.

[0304] The improvement in idiopathic sleep disturbance, 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.

[0305] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0306] In the case of idiopathic sleep disorder, improvement in the sleep disorder, as reflected by a reduction in the CGI-I score or PGI-I score by at least a "much improved" score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0307] Improvement in sleep disorders can also be assessed by any other measure that reflects changes in the quality or quantity of sleep as described above, for example, the Pittsburgh Sleep Quality Index (PSQI).

[0308] 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.

[0309] Improvement in sleep disturbance, as reflected by a reduction in PSQI score, particularly a reduction to 5 or less, preferably occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute psychedelic experience has waned between the last administration and the time of assessment.

[0310] The improvement in sleep disturbance, as reflected by a reduction in PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the recall period begins no earlier than the time the acute psychedelic experience between the last administration and the time of assessment has worn off.

[0311] 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, and the recall period begins no earlier than the time the acute psychedelic experience has waned between the last administration and the time of assessment.

[0312] Anxiety and sleep disorders, especially insomnia, are closely related to psychiatric and nervous system disorders. Both anxiety and sleep disorders, especially insomnia, are related to psychiatric or nervous system disorders, for example, disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders, somatic symptom 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), and post-traumatic stress disorder. (PTSD), pain disorders such as chronic pain, fibromyalgia and migraine, mental and behavioral disorders resulting from the use of psychoactive substances such as substance use disorders (SUD), psychotic disorders such as schizophrenia, Parkinson's disease, or schizotypal personality disorder, dementia such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia, Parkinson's disease (PD), eating disorders, attention deficit hyperactivity disorder (ADHD), personality disorders such as schizotypal personality disorder and borderline personality disorder, autism spectrum disorder, chronic fatigue syndrome.

[0313] Both anxiety and sleep disorders, particularly insomnia, occur in medical health conditions that are linked to related mental or neurological conditions, such as HIV, traumatic brain injury, or post-COVID symptoms.

[0314] Treatment according to the present invention improves both anxiety and sleep disorders, particularly insomnia, as well as related psychiatric or nervous system disorders (examples of which are listed above), and, as explained above, psychiatric or nervous system conditions associated with certain medical conditions.

[0315] Treatment of anxiety and mental and nervous system disorders Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0316] A depressive episode is a period of depressed mood and / or loss of enjoyment in most activities.

[0317] For example, according to the DSM-V, a major depressive episode is characterized by five or more symptoms present during the same two-week period and representing a change from previous functioning, at least one of which is either (1) depressed mood or (2) loss of interest or enjoyment.

[0318] Patients suffering from a disorder characterized by depressive episodes may suffer from treatment-resistant versions of the disorder.

[0319] Patients suffering from a disorder characterized by depressive episodes may also exhibit symptoms of anxiety without being diagnosed as suffering from an anxiety disorder (subthreshold anxiety).

[0320] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0321] A patient may also be diagnosed with a disorder characterized by depressive episodes and may also be diagnosed with an anxiety disorder, i.e., be considered to have a comorbidity of the disorder and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0322] Anxiety symptoms in patients with a disorder characterized by depressive episodes, such as those with the disorder and subthreshold anxiety, or those with comorbidities of the disorder and anxiety, are associated with more severe depression and increased frequency of suicidal ideation.

[0323] Anxiety in patients suffering from disorders characterized by depressive episodes can be assessed using the Hamilton Rating Scale for Anxiety (HAM-A), the psychic anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), the Beck Anxiety Inventory (BAI), the anxiety / somatization factor of the Hamilton Rating Scale for Depression (HAM-D) (sum of items: anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), hypochondriasis, and insight), the HAM-D items "psychic anxiety" and / or "somatic anxiety," the Montgomery-Asberg Depression Rating Scale (MADRS) item "inner tension," and the Brief Psychiatric Rating Scale (BPRS) item "anxiety."

[0324] Suicidal ideation can be assessed using the MADRS item "suicidal thoughts" or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0325] In patients suffering from disorders characterized by depressive episodes, alterations in the functional connectivity within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal are observed.Anxiety is also associated with abnormalities in the connectivity within and / or between resting-state networks, such as the default mode network and the salience network.These abnormalities in connectivity can be normalized by treatment according to the present invention.

[0326] Treating a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who has anxiety symptoms, e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient suffering from such a disorder and co-morbid anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety, resulting in improvement of the disorder.

[0327] The reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such a disorder), e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient with a comorbid disorder and anxiety, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0328] In patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who also have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with such a disorder and co-morbid anxiety, the reduction or elimination of anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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] A reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such a disorder) and who has anxiety symptoms, e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient suffering from such a disorder and comorbid anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0330] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0331] A reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such a disorder) and who has anxiety symptoms, e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient suffering from such a disorder and comorbid anxiety, as reflected by a reduction in the score on the Psychiatric Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0332] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant cases of the disorder) and who have anxiety symptoms, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0333] A reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including a treatment-resistant version of the disorder) and who has anxiety symptoms, e.g., a patient suffering from the disorder and subthreshold anxiety, or a patient suffering from a comorbid disorder and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0334] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with such a disorder and co-morbid anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0335] A reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such a disorder), e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient with a comorbid disorder and anxiety, as reflected by a reduction in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0336] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0337] A reduction or elimination of anxiety in patients with a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have symptoms of anxiety, e.g., patients with such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a reduction in the score on the HAM-D items "mental anxiety" and / or "somatic anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0338] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with such a disorder and comorbid anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0339] A reduction or elimination of anxiety in patients with a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients with such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a decrease in the score on the MADRS item "internal tension," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0340] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," preferably persists for at least 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.

[0341] A reduction or elimination of anxiety in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such a disorder) and who has symptoms of anxiety, e.g., a patient suffering from such a disorder and subthreshold anxiety, or a patient suffering from such a disorder and comorbid anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0342] The reduction or elimination of anxiety in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and who have anxiety symptoms, e.g., patients suffering from such a disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0343] A clinical response in a patient suffering from a disorder characterized by depressive episodes and subthreshold anxiety is reflected by at least a 50% decrease in the HAM-D score and a decrease in the HAM-A score to 7 or less, compared to the respective scores before treatment, 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.

[0344] A clinical response in patients suffering from a disorder characterized by depressive episodes and subthreshold anxiety, reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] The clinical response in patients suffering from a disorder characterized by depressive episodes and subthreshold anxiety, as reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, preferably persists for at least 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.

[0346] A clinical response in a patient with a disorder characterized by a depressive episode and a comorbid disorder of anxiety is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0347] The clinical response of a patient having a disorder characterized by a depressive episode and a comorbid anxiety disorder, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of a patient having a disorder characterized by a depressive episode and a comorbid anxiety disorder, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A 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.

[0348] Remission in a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and subthreshold anxiety, or a patient with such a disorder (including treatment-resistant such disorders) and a comorbid condition of anxiety, is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less 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.

[0349] Remission in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and subthreshold anxiety, or in patients with such a disorder (including treatment-resistant such disorders) and a comorbid anxiety disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0350] Treating patients suffering from a disorder characterized by depressive episodes (including treatment-resistant such disorders) and subthreshold anxiety, or patients with such a disorder (including treatment-resistant such disorders) and a comorbid condition of anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0351] A reduction or elimination of suicidal ideation in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant versions of such a disorder) and subthreshold anxiety, or in patients with such a disorder (including treatment-resistant versions of such a disorder) and a comorbid condition of anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0352] The reduction or elimination of suicidal ideation in patients suffering from a disorder characterized by depressive episodes (including treatment-resistant versions of such a disorder) and subthreshold anxiety, or in patients with such a disorder (including treatment-resistant versions of such a disorder) and a comorbid condition of anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0353] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects a person's emotions, thoughts, and behaviors and can lead to a variety of emotional and physical problems.

[0354] Patients with MDD may suffer from treatment-resistant forms of the disorder.

[0355] Patients suffering from MDD may also exhibit symptoms of anxiety without being diagnosed as suffering from an anxiety disorder (subthreshold anxiety). As the term is used herein, such patients suffer from anxiety depression.

[0356] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0357] A patient may also be diagnosed with MDD and further diagnosed with anxiety, i.e., may be considered to have comorbid anxiety and depression (rather than anxious depression). Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0358] Anxiety symptoms in patients with MDD, such as those with anxiety depression or those with comorbid anxiety and depression, are associated with more severe depression and increased frequency of suicidal ideation.

[0359] Anxiety in patients with MDD can be assessed using the Hamilton Rating Scale for Anxiety (HAM-A), the psychic anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), the Beck Anxiety Inventory (BAI), the anxiety / somatization factor of the Hamilton Rating Scale for Depression (HAM-D) (sum of items: anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), hypochondriasis, and insight), the HAM-D items "psychic anxiety" and / or "somatic anxiety," the Montgomery-Asberg Depression Rating Scale (MADRS) item "inner tension," and the Brief Psychiatric Rating Scale (BPRS) item "anxiety."

[0360] Suicidal ideation can be assessed using the MADRS item "suicidal thoughts" or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0361] In patients with MDD, dysfunctional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network, are observed. Functional connectivity is significantly different from that observed in healthy controls. Anxiety is also associated with abnormal connectivity within and / or between resting-state networks, such as the default mode network and the salience network. This abnormal connectivity can be normalized by treatment according to the present invention.

[0362] Treating patients with MDD (including treatment-resistant forms of the disorder) and who have symptoms of anxiety, such as patients with anxiety depression or patients with comorbid anxiety and MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety, resulting in improvement of the MDD.

[0363] In patients with MDD (including treatment-resistant forms of the disorder) and with anxiety symptoms, e.g., patients with anxiety depression, or patients with comorbid anxiety and MDD, a reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0364] In patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, such as patients with anxiety-related depression or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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.

[0365] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and with anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and MDD, as reflected by a decrease in HAM-A score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0366] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and MDD, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A 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.

[0367] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxiety-depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 29 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0368] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0369] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of such a disorder) and with anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0370] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0371] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of such disorders) and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, as reflected by a reduction in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0372] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression or patients with comorbid anxiety and MDD, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 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] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxiety depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at day 7, at day 14, at day 28, and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and with anxiety symptoms, e.g., patients with anxiety depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0375] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxiety depression, or patients with comorbid anxiety and MDD, as reflected by a decrease in the score on the MADRS item "internal tension," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0376] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the MADRS item "inner tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0377] A reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and with symptoms of anxiety, e.g., patients with anxiety depression, or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the BPRS item "Anxiety," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0378] The reduction or elimination of anxiety in patients with MDD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0379] A clinical response in a patient suffering from anxiety-depression is reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, compared to the respective scores before treatment, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0380] The clinical response of a patient suffering from anxiety and depression, as reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of a patient suffering from anxiety and depression, as reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0381] Clinical response in patients with comorbid anxiety and MDD is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A score, compared to the respective scores before treatment, 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.

[0382] The clinical response in patients with comorbid anxiety and MDD, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients with comorbid anxiety and MDD, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0383] Remission of anxiety depression or comorbid anxiety and MDD (including treatment-resistant such disorders) in a patient suffering from such disorder is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less 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, 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0384] Remission of anxiety-depression or a comorbid disorder of anxiety and MDD (including treatment-resistant disorders) in a patient suffering from such a disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety-depression or a comorbid disorder of anxiety and MDD (including treatment-resistant disorders) in a patient suffering from such a disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0385] Treating patients with MDD (including treatment-resistant forms of the disorder) and who have anxiety symptoms, e.g., patients who have anxiety depression, or patients who have comorbid anxiety and MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0386] A reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and MDD (including treatment-resistant such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] The reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and MDD (including treatment-resistant forms of such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and MDD (including treatment-resistant forms of such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," preferably persists for at least 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] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks of giving birth. Although over 50% of women may experience a short period of low mood or tearfulness after giving birth, a subset of women may develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0389] The patient may have moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or greater. It is further contemplated that the patient may have severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or greater.

[0390] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0391] Additionally, patients treated according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0392] Moreover, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0393] Patients with PPD may suffer from treatment-resistant forms of the disorder.

[0394] Anxiety symptoms are a prominent feature of PPD and are significantly more common in women who experience postnatal depression than in women who do not.

[0395] The added burden of anxiety symptoms may be due to the responsibilities of caring for a newborn and significant sleep deprivation.

[0396] Both depression and anxiety during the postpartum period not only affect the mother's overall sense of well-being, but also the way she interacts with her child and, therefore, the child's development.

[0397] PPD can be assessed by the Edinburgh Postnatal Depression Questionnaire (EPDS), a scale that assesses how the mother has felt over the past seven days. Anxiety is assessed in three of the ten questions assessed in the questionnaire. The range of ratings is from "0" (no, not at all) to "3" (yes, most of the time). With a threshold level of a total score of 13, anxiety can be considered a fundamental part of the PPD diagnosis.

[0398] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, emotion, and cognition. PPD is associated with dysfunction in resting-state network connectivity, for example, within and / or between the default mode network and the frontoparietal network.

[0399] Anxiety is also associated with abnormalities in connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which can be normalized by treatment according to the present invention.

[0400] Treating patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety depression, or patients with comorbid anxiety and PPD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the PPD.

[0401] In patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety depression, or patients with comorbid anxiety and PPD, reduction or elimination of anxiety is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0402] In patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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.

[0403] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and PPD, as reflected by a decrease in HAM-A score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0404] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety-depression or patients with comorbid anxiety and PPD, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A 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.

[0405] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0406] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxiety-depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0407] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such a disorder) and with anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0408] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0409] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the Anxiety / Somatization factor on the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0410] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxiety-depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 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.

[0411] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0412] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 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.

[0413] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxiety depression, or patients with comorbid anxiety and PPD, as reflected by a decrease in the score on the MADRS item "internal tension," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0414] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the MADRS item "internal tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "internal tension," preferably persists for at least 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.

[0415] A reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such a disorder) and with symptoms of anxiety, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0416] The reduction or elimination of anxiety in patients with PPD (including treatment-resistant forms of such disorders) and anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0417] A clinical response in a patient suffering from anxiety-depression is reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, compared to the respective scores before treatment, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on the first day, e.g., about 24 hours, on the 7th day, the 14th day, and / or the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0418] The clinical response of a patient suffering from anxiety and depression, as reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of a patient suffering from anxiety and depression, as reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, preferably persists for at least 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] Clinical response in patients with comorbid anxiety and PPD is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A score, compared to the respective scores before treatment, 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.

[0420] The clinical response of patients with comorbid anxiety and PPD, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of patients with comorbid anxiety and PPD, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A 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.

[0421] Remission of anxiety depression or comorbid anxiety and PPD in a patient suffering from such a disorder (including treatment-resistant such disorders) is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0422] Remission of anxiety-depression or a comorbid disorder of anxiety and PPD (including treatment-resistant disorders) in a patient suffering from such a disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety-depression or a comorbid disorder of anxiety and PPD (including treatment-resistant disorders) in a patient suffering from such a disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0423] Treating patients with PPD (including treatment-resistant forms of the disorder) and anxiety symptoms, e.g., patients with anxiety depression or patients with comorbid anxiety and PPD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0424] A reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and PPD (including treatment-resistant such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0425] The reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and PPD (including treatment-resistant forms of such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thinking," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation in patients suffering from anxiety depression or a comorbid disorder of anxiety and PPD (including treatment-resistant forms of such disorders), as reflected by a reduction in the score on the MADRS item "Suicidal Thinking," preferably persists for at least 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.

[0426] Anxiety further impairs maternal function.

[0427] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index was designed to measure functioning in the year following childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6, with a maximum total score of 120. Higher scores indicate better maternal functioning.

[0428] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0429] A BIMF score of 95 or less is considered herein to represent a mild impairment of maternal functioning, a score of 80 or less is considered herein to represent a severe impairment of maternal functioning, and a score of 65 or less is considered herein to represent a severe impairment of maternal functioning.

[0430] The inventors determined that elevated scores on the BPRS item "anxiety" and / or the MADRS item "internal tension" negatively impact maternal functioning (mother's ability to interact with her infant(s) and maternal self-care).

[0431] In particular, the inventors have determined that elevated scores on the BPRS item "Anxiety" negatively impact both aspects of maternal functioning (the mother's ability to interact with her infant(s) and her self-care). Elevated scores on the BPRS item "Anxiety" are associated with impaired psychological well-being, social support, and control.

[0432] Conversely, improvement on this BPRS item would translate to improvement in maternal functioning, particularly the BIMF functioning domains of psychological well-being, social support, and / or control.

[0433] Furthermore, the inventors have determined that elevated scores on the MADRS item "internal strain" negatively impact both aspects of maternal functioning (the mother's ability to interact with her infant(s) and her self-care). Elevated scores on the MADRS item "internal strain" impair mother-infant interaction and maternal psychological well-being as assessed by the BIMF.

[0434] Conversely, improvements on these MADRS items would translate to improvements in maternal functioning, particularly the BIMF functional domains of mother-infant interaction and / or maternal psychological well-being.

[0435] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in anxiety.

[0436] We further conclude that the reduction or elimination of anxiety by treatment in PPD patients leads not only to a decrease in the MADRS total score but also to an improvement in maternal functioning as reflected by an increase in the BIMF score.

[0437] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0438] 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.

[0439] The 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.

[0440] Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. Persistent depressive disorder is diagnosed when a person is depressed for most of the day for at least two years. Any symptom-free period lasts less than two months.

[0441] During a depression, two or more of the following must be 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 difficulty concentrating.

[0442] Patients suffering from persistent depressive disorder may suffer from treatment-resistant version of the disorder.

[0443] Patients suffering from persistent depressive disorder may also exhibit symptoms of anxiety without being diagnosed as suffering from an anxiety disorder (subthreshold anxiety).

[0444] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0445] A patient may also have been diagnosed with persistent depressive disorder and may also have been diagnosed with anxiety, i.e., be considered to have a comorbidity of the disorder and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0446] Anxiety symptoms in patients with persistent depressive disorder, such as those with the disorder and subthreshold anxiety, or those with comorbidities of the disorder and anxiety, are associated with more severe depression and increased frequency of suicidal ideation.

[0447] Anxiety in patients with persistent depressive disorder can be assessed using the Hamilton Rating Scale for Anxiety (HAM-A), the psychic anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), the Beck Anxiety Inventory (BAI), the anxiety / somatization factor of the Hamilton Rating Scale for Depression (HAM-D) (sum of items: anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), hypochondriasis, and insight), the HAM-D items "psychic anxiety" and / or "somatic anxiety," the Montgomery-Asberg Depression Rating Scale (MADRS) item "inner tension," and the Brief Psychiatric Rating Scale (BPRS) item "anxiety."

[0448] Suicidal ideation can be assessed using the MADRS item "suicidal thoughts" or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0449] In patients with persistent depressive disorder, alterations in functional connectivity within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal are observed. Connectivity dysfunction is 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.

[0450] Anxiety is also associated with abnormalities in connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which can be normalized by treatment according to the present invention.

[0451] Treating patients with persistent depressive disorder (including treatment-resistant such disorder) and anxiety symptoms, such as patients with such disorder and subthreshold anxiety, or patients with such disorder and co-morbid anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety, resulting in improvement of the disorder.

[0452] The reduction or elimination of anxiety in patients suffering from persistent depressive disorder (including treatment-resistant such disorder), e.g., patients suffering from such disorder and subthreshold anxiety, or patients with comorbidities of such disorder and anxiety, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] In patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, such as patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, the reduction or elimination of anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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] A reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant such disorder) and anxiety symptoms, e.g., patients with such disorder and subthreshold anxiety, or patients with comorbidities of such disorder and anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0455] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A 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.

[0456] A reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0458] A reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant such disorder) and anxiety symptoms, e.g., patients with such disorder and subthreshold anxiety, or patients with comorbidities of such disorder and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0459] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0460] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder), e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0461] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 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] A reduction or elimination of anxiety in patients with a persistent depressive disorder (including a treatment-resistant version of the disorder) and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0463] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 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] A reduction or elimination of anxiety in patients with a persistent depressive disorder (including treatment-resistant such disorders) and with anxiety symptoms, e.g., patients with such a disorder and subthreshold anxiety, or patients with comorbidities of such a disorder and anxiety, as reflected by a decrease in the score on the MADRS item "inner tension," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 29 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0465] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," preferably persists for at least 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] A reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant such disorder) and with symptoms of anxiety, e.g., patients with such disorder and subthreshold anxiety, or patients with comorbidities of such disorder and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0467] The reduction or elimination of anxiety in patients with persistent depressive disorder (including treatment-resistant depressive disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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] A clinical response in patients suffering from persistent depressive disorder and subthreshold anxiety is reflected by at least a 50% decrease in the HAM-D score and a decrease in the HAM-A score to 7 or less, compared to the respective scores before treatment, 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.

[0469] A clinical response in patients suffering from persistent depressive disorder and subthreshold anxiety, reflected by at least a 50% reduction in the HAM-D score compared to the respective scores before treatment and a reduction in the HAM-A score to 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0470] The clinical response in patients with persistent depressive disorder and subthreshold anxiety, as reflected by at least a 50% reduction in HAM-D score and a reduction in HAM-A score to 7 or less, preferably persists for at least 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.

[0471] Clinical response in patients with persistent depressive disorder and comorbid anxiety is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A score, compared to the respective scores before treatment, 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.

[0472] The clinical response in patients with persistent depressive disorder and comorbid anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients with persistent depressive disorder and comorbid anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A 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.

[0473] Remission in a patient suffering from a persistent depressive disorder (including treatment-resistant such a disorder) and subthreshold anxiety, or a patient with a comorbid disorder (including treatment-resistant such a disorder) and anxiety, is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less 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, 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0474] Remission in patients suffering from persistent depressive disorder (including treatment-resistant depressive disorder) and subthreshold anxiety, or patients with such a disorder (including treatment-resistant depressive disorder) and a comorbid anxiety disorder, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0475] Treating patients with persistent depressive disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or patients with such a disorder (including treatment-resistant forms of the disorder) and the comorbidity of anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0476] A reduction or elimination of suicidal ideation in patients with persistent depressive disorder (including treatment-resistant forms of such disorder) and subthreshold anxiety, or patients with a comorbid disorder (including treatment-resistant forms of such disorder) and anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0477] The reduction or elimination of suicidal ideation in patients with persistent depressive disorder (including treatment-resistant forms of such disorder) and subthreshold anxiety, or patients with the comorbidity of such disorder (including treatment-resistant forms of such disorder) and anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," preferably persists for at least 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.

[0478] 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.

[0479] Patients suffering from seasonal affective disorder may suffer from treatment-resistant versions of the disorder.

[0480] Patients suffering from seasonal affective disorder may also exhibit symptoms of anxiety without being diagnosed as suffering from an anxiety disorder (subthreshold anxiety).

[0481] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0482] A patient may also be diagnosed with seasonal affective disorder and may also be diagnosed with an anxiety disorder, i.e., be considered to have a comorbidity of the disorder and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0483] Anxiety symptoms in patients with seasonal affective disorder, such as those with the disorder and subthreshold anxiety, or those with comorbidities of the disorder and anxiety, are associated with more severe depression and increased frequency of suicidal ideation.

[0484] Anxiety in patients suffering from seasonal affective disorder can be assessed using the Hamilton Rating Scale for Anxiety (HAM-A), the psychic anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), the Beck Anxiety Inventory (BAI), the anxiety / somatization factor of the Hamilton Rating Scale for Depression (HAM-D) (sum of items: anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), hypochondriasis, and insight), the HAM-D items "psychic anxiety" and / or "somatic anxiety," the Montgomery-Asberg Depression Rating Scale (MADRS) item "inner tension," and the Brief Psychiatric Rating Scale (BPRS) item "anxiety."

[0485] Suicidal ideation can be assessed using the MADRS item "suicidal thoughts" or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0486] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0487] Anxiety is also associated with abnormalities in connectivity within and / or between resting-state networks, such as the default mode network, the salience network, and the sensorimotor network, which can be normalized by treatment according to the present invention.

[0488] Treating patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, such as patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety, resulting in improvement of the disorder.

[0489] The reduction or elimination of anxiety in patients suffering from seasonal affective disorder (including treatment-resistant seasonal affective disorder), e.g., patients suffering from the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0490] In patients suffering from seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients suffering from the disorder and subthreshold anxiety, or patients suffering from the disorder and co-morbid anxiety, the reduction or elimination of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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.

[0491] A reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in HAM-A score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0492] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A 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] A reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the Mental Anxiety subscale (sum of items 1-6 and 14) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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] A reduction or elimination of anxiety in a patient with seasonal affective disorder (including a treatment-resistant version of the disorder) and with anxiety symptoms, e.g., a patient with the disorder and subthreshold anxiety, or a patient with a comorbid disorder and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0496] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder), e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 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] A reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0500] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 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] A reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a decrease in the score on the MADRS item "inner tension," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0502] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "inner tension," preferably persists for at least 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] A reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and with symptoms of anxiety, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., at about 24 hours, at day 7, at day 14, at day 28, and / or at day 29 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0504] The reduction or elimination of anxiety in patients with seasonal affective disorder (including treatment-resistant seasonal affective disorder) and anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbidities of the disorder and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0505] A clinical response in a patient suffering from seasonal affective disorder and subthreshold anxiety is reflected by at least a 50% decrease in the HAM-D score and a decrease in the HAM-A score to 7 or less, compared to the respective scores before treatment, 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.

[0506] A clinical response in patients suffering from seasonal affective disorder and subthreshold anxiety, reflected by at least a 50% reduction in the HAM-D score compared to the respective scores before treatment and a reduction in the HAM-A score to 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] The clinical response in patients suffering from seasonal affective disorder and subthreshold anxiety, as reflected by at least a 50% reduction in HAM-D score and a reduction in HAM-A score to 7 or less, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0508] The clinical response in patients with comorbid seasonal affective disorder and anxiety is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0509] The clinical response of patients with comorbid seasonal affective disorder and anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of patients with comorbid seasonal affective disorder and anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A 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.

[0510] Remission in a patient suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or a patient with a comorbid disorder (including treatment-resistant forms of the disorder) and anxiety, is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less 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.

[0511] Remission in patients suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or in patients with such a disorder (including treatment-resistant forms of the disorder) and a comorbid condition of anxiety, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0512] Treating patients with seasonal affective disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or patients with such disorders (including treatment-resistant forms of the disorder) and the comorbidity of anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0513] A reduction or elimination of suicidal ideation in patients with seasonal affective disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or patients with a comorbid disorder (including treatment-resistant forms of the disorder) and anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0514] The reduction or elimination of suicidal ideation in patients with seasonal affective disorder (including treatment-resistant forms of the disorder) and subthreshold anxiety, or patients with the comorbid disorder (including treatment-resistant forms of the disorder) and anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thinking," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by a reduction in the score on the MADRS item "Suicidal Thinking," preferably persists for at least 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] Bipolar disorder 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 disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0516] 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.

[0517] Patients with BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0518] Patients suffering from BD, whether diagnosed with bipolar II disorder or bipolar I disorder, specifically suffer from a current major depressive episode.

[0519] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient's total score can be 19 or higher, for example 24 or higher, particularly 37 or higher.

[0520] Alternatively, or in addition, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as 24 or greater, particularly 37 or greater.

[0521] Anxiety symptoms are common in BD, and patients with BD are more often diagnosed with comorbid anxiety disorders than with depression.

[0522] Anxiety is also a commonly reported feature of certain manic episodes, sometimes later referred to as "mixed symptoms."

[0523] Patients with BD may also exhibit symptoms of anxiety without being diagnosed as having an anxiety disorder (subthreshold anxiety).

[0524] As used herein, the term "subthreshold anxiety" specifically refers to a patient having a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 (but less than 18) and / or a Beck Anxiety Inventory (BAI) score of at least 11 (but less than 16).

[0525] A patient may also be diagnosed with BD and may also be diagnosed with anxiety, i.e., be considered to have comorbid BD and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0526] The presence of comorbid anxiety symptoms is important to identify, as comorbid anxiety increases the risk of suicide in patients with bipolar disorder.

[0527] Anxiety in patients with BD can be assessed using the Hamilton Rating Scale for Anxiety (HAM-A), the psychic anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), the Beck Anxiety Inventory (BAI), the anxiety / somatization factor of the Hamilton Rating Scale for Depression (HAM-D) (sum of items: anxiety (psychic), anxiety (somatic), somatic symptoms (gastrointestinal), somatic symptoms (general), hypochondriasis, and insight), the HAM-D items "psychic anxiety" and / or "somatic anxiety," the Montgomery-Asberg Depression Rating Scale (MADRS) item "inner tension," the Bipolar Depression Rating Scale (BDRS) item "anxiety," and the Brief Psychiatric Rating Scale (BPRS) item "anxiety."

[0528] Suicidal ideation can be assessed using the MADRS item "suicidal thoughts," the BDRS item "suicidal ideation," or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0529] Patients with bipolar disorder exhibit characteristic abnormal intrinsic organization and interconnectivity of resting-state networks. Compared to healthy controls, resting-state functional magnetic resonance imaging studies demonstrated altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network.

[0530] Anxiety is also associated with abnormalities in connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which can be normalized by treatment according to the present invention.

[0531] Treatment of patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of BD.

[0532] Reduction or elimination of anxiety in patients with BD (including treatment-resistant BD), e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0533] In patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, the reduction or elimination of anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety preferably persists for at least 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.

[0534] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a decrease in HAM-A score, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a decrease in HAM-A score, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in HAM-A 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.

[0536] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the HAM-A Psychiatric Anxiety subscale (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0538] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0540] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD), e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0541] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the anxiety / somatization factor on the HAM-D, preferably persists for at least 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] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0543] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-D items "Mental Anxiety" and / or "Somatic Anxiety," preferably persists for at least 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.

[0544] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a decrease in the score on the MADRS item "internal tension," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the MADRS item "internal tension," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the MADRS item "internal tension," preferably persists for at least 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.

[0546] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the BDRS item "Anxiety," is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the BDRS item "Anxiety," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the BDRS item "Anxiety," preferably persists for at least 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.

[0548] A reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0549] The reduction or elimination of anxiety in patients with BD (including treatment-resistant BD) and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0550] Clinical response in patients suffering from BD and subthreshold anxiety is reflected by at least a 50% reduction in the HAM-D score and a reduction in the HAM-A score to 7 or less, compared to the respective scores before treatment, at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0551] A clinical response in patients suffering from BD and subthreshold anxiety, reflected by at least a 50% reduction in the HAM-D score compared to the respective scores before treatment and a reduction in the HAM-A score to 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0552] The clinical response in patients suffering from BD and subthreshold anxiety, as reflected by at least a 50% reduction in HAM-D score and a reduction in HAM-A score to 7 or less, preferably persists for at least 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.

[0553] Clinical response in patients with comorbid BD and anxiety is reflected by at least a 50% decrease in the HAM-D score and at least a 50% decrease in the HAM-A score, compared to the respective scores before treatment, 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.

[0554] The clinical response of patients with comorbid BD and anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A score compared to the respective scores before treatment, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response of patients with comorbid BD and anxiety, as reflected by at least a 50% reduction in the HAM-D score and at least a 50% reduction in the HAM-A 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.

[0555] Remission in patients suffering from BD (including treatment-resistant BD) and subthreshold anxiety, or patients with the comorbidities of BD (including treatment-resistant such disorders) and anxiety, is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less 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, 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] Remission in patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with comorbid BD (including treatment-resistant such disorders) and anxiety, as reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less preferably lasts for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] Treating patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with BD (including treatment-resistant versions of the disorder) and the comorbid disorder of anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0558] Reduction or elimination of suicidal ideation in patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with BD (including treatment-resistant such disorders) and the comorbid disorder of anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] The reduction or elimination of suicidal ideation in patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with comorbid BD (including treatment-resistant such disorders) and anxiety, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," preferably persists for at least 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.

[0560] Reduction or elimination of suicidal ideation in patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with BD (including treatment-resistant such disorders) and the comorbid disorder of anxiety, as reflected by a reduction in the score on the BDRS item "Suicidal Ideation," is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, at 7 days, at 14 days, and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] The reduction or elimination of suicidal ideation in patients with BD (including treatment-resistant BD) and subthreshold anxiety, or patients with BD (including treatment-resistant such disorders) and the comorbid disorder of anxiety, as reflected by a reduction in the score on the BDRS item "Suicidal Ideation," occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation, as reflected by a reduction in the score on the BDRS item "Suicidal Ideation," preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0562] Anxiety disorder Anxiety is a mental health condition. Symptoms include tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system associated with preparation for an anticipated event or situation that is perceived as threatening.

[0563] Patients suffering from anxiety disorders may suffer from treatment-resistant versions of the disorder.

[0564] Severity of anxiety can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0565] Anxiety is also associated with suicidal thoughts.

[0566] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0567] Anxiety disorders are examined by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). Additional networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting balance within and / or between each of these networks (e.g., SMN and SN) relative to the DMN may show abnormalities in different anxiety disorders.

[0568] Treating a patient suffering from an anxiety disorder (including treatment-resistant such disorders) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0569] The reduction or elimination of anxiety in a patient suffering from an anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0570] The reduction or elimination of anxiety 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.

[0571] A clinical response in a patient suffering from an anxiety disorder (including treatment-resistant such disorders) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0572] In patients suffering from anxiety disorders (including treatment-resistant forms of such disorders), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from anxiety disorders (including treatment-resistant forms of such disorders), a clinical response reflected by at least a 50% reduction in the HAM-A 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.

[0573] Remission of anxiety in a patient suffering from such an anxiety disorder (including treatment-resistant such disorders) is reflected by a HAM-A score of 7 or less 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.

[0574] Relief of anxiety in patients suffering from such anxiety disorders (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety in patients suffering from such anxiety disorders (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, preferably persists for at least 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.

[0575] A reduction or elimination of anxiety in a patient suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0576] The reduction or elimination of anxiety in patients suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a reduction in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0577] A reduction or elimination of anxiety in a patient suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0578] The reduction or elimination of anxiety in patients suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0579] A reduction or elimination of anxiety in a patient suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0580] The reduction or elimination of anxiety in patients suffering from an anxiety disorder (including treatment-resistant such disorders), as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0581] Treating patients suffering from anxiety disorders (including treatment-resistant such disorders) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0582] Reduction or elimination of suicidal ideation in patients suffering from an anxiety disorder (including treatment-resistant such disorders) is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] The reduction or elimination of suicidal ideation in patients suffering from anxiety disorders (including treatment-resistant forms of such disorders) occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] The above applies generally to anxiety disorders, such as the specific conditions discussed below, as well as anxiety disorders due to medical conditions (which arise when a medical condition causes extreme fear, anxiety, or panic), other specific anxiety disorders (which may be diagnosed when a patient has most, but not all, of the criteria for an anxiety disorder), and unspecified anxiety disorders (which are often diagnosed when a patient is experiencing anxiety or panic but there is a lack of information to make a full diagnosis of another anxiety disorder).

[0585] Separation anxiety disorder is characterized by excessive anxiety about separation from home and / or from people to whom the sufferer has strong emotional attachments.

[0586] The separation situation may cause significant distress to the patient, making it difficult for the patient to attend school or work. Patients with separation anxiety disorder may also have excessive anxiety about unwanted events happening to important people in their lives, such as family members.

[0587] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0588] The severity of separation anxiety can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0589] Separation anxiety is also associated with suicidal thoughts.

[0590] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0591] Separation anxiety disorder is examined by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). Additional networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting balance within and / or between each of these networks (e.g., SMN and SN) relative to the DMN may show abnormalities in different anxiety disorders.

[0592] Treating patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0593] The reduction or elimination of anxiety in a patient suffering from separation anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0594] The reduction or elimination of anxiety 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.

[0595] A clinical response in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0596] In patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A 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] Remission of anxiety in a patient suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

[0598] Amelioration of anxiety in patients suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Amelioration of anxiety in patients suffering from such separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, preferably persists for at least 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] A reduction or elimination of anxiety in patients with separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the Psychological Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] The reduction or elimination of anxiety in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the HAM-A Psychological Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0601] A reduction or elimination of anxiety in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] The reduction or elimination of anxiety in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, preferably persists for at least 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.

[0603] A reduction or elimination of anxiety in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] The reduction or elimination of anxiety in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0605] Treating patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0606] Reduction or elimination of suicidal ideation in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0607] The reduction or elimination of suicidal ideation in patients suffering from separation anxiety disorder (including treatment-resistant forms of the disorder) occurs within about 2 hours of 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.

[0608] Agoraphobia is the fear of situations or places that can cause feelings of panic, claustrophobia, helplessness, or shame.

[0609] Patients with agoraphobia may find it difficult to leave the house. The idea of ​​leaving the house can cause so much anxiety that it becomes avoided. Fear of crowds, travel, elevators, movie theaters, malls, etc. can cause significant difficulties.

[0610] Patients with agoraphobia may also have recurrent panic attacks.

[0611] Patients suffering from agoraphobia may suffer from a treatment-resistant form of the disorder.

[0612] The severity of agoraphobia can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0613] Agoraphobia has also been associated with suicidal thoughts.

[0614] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0615] Functional magnetic resonance imaging in individuals with agoraphobia reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0616] Treating patients suffering from agoraphobia (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0617] The reduction or elimination of anxiety in a patient suffering from agoraphobia is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 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.

[0618] The reduction or elimination of anxiety in a patient suffering from agoraphobia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] A clinical response in a patient suffering from agoraphobia (including treatment-resistant forms of the disorder) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0620] In patients suffering from agoraphobia (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from agoraphobia (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A 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] Remission of anxiety in a patient suffering from such agoraphobia (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

[0622] Relief of anxiety in patients suffering from such agoraphobia (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety in patients suffering from such agoraphobia (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, preferably persists for at least 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.

[0623] A reduction or elimination of anxiety in patients with agoraphobia (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0624] The reduction or elimination of anxiety in patients suffering from agoraphobia (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0625] A reduction or elimination of anxiety in patients with agoraphobia (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0626] The reduction or elimination of anxiety in patients suffering from agoraphobia (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, preferably persists for at least 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.

[0627] A reduction or elimination of anxiety in patients with agoraphobia (including treatment-resistant forms of the disorder), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] The reduction or elimination of anxiety in patients suffering from agoraphobia (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0629] Treating patients suffering from agoraphobia (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0630] Reduction or elimination of suicidal ideation in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0631] The reduction or elimination of suicidal ideation in patients suffering from agoraphobia (including treatment-resistant forms of the disorder) occurs within about 2 hours of 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.

[0632] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and difficult-to-control worry about a wide range of situations and problems. People with GAD may expect the worst and worry excessively about money, health, family, work, or other problems.

[0633] GAD is diagnosed when an individual experiences persistent worry about everyday challenges that is out of proportion to the perceived threat. Patients with GAD typically experience excessive fear that lasts for months or even years.

[0634] GAD interferes with social, occupational, or other important areas of functioning.

[0635] Patients with GAD may suffer from treatment-resistant forms of the disorder.

[0636] The severity of GAD can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0637] GAD is also associated with suicidal ideation.

[0638] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0639] Patients with GAD also show altered functional connectivity, particularly within the default mode network.

[0640] Treating patients suffering from GAD (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0641] The reduction or elimination of anxiety in a patient with GAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] The reduction or elimination of anxiety 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.

[0643] A clinical response in patients suffering from GAD (including treatment-resistant forms of the disorder) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0644] In patients suffering from GAD (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from GAD (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] Remission of anxiety in such patients suffering from GAD (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

[0646] Relief of anxiety in patients suffering from such GAD (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety in patients suffering from such GAD (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] A reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0648] The reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0649] A reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0650] The reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, preferably persists for at least 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.

[0651] A reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0652] The reduction or elimination of anxiety in patients with GAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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.

[0653] Treating patients suffering from GAD (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0654] Reduction or elimination of suicidal ideation in patients with GAD (including treatment-resistant forms of the disorder) is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0655] The reduction or elimination of suicidal ideation in patients with GAD (including treatment-resistant forms of the disorder) occurs within about 2 hours of 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.

[0656] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety.

[0657] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations, which often leads to avoidance of social situations and can cause impairment in school, work, or relationships.

[0658] Patients with SAD may suffer from treatment-resistant forms of the disorder.

[0659] Severity of SAD can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0660] SAD is also associated with suicidal thoughts.

[0661] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0662] In patients with SAD, alterations in functional connectivity within and / or between resting-state networks, such as the default mode network and the salience network, are observed.

[0663] Treating patients suffering from SAD (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0664] The reduction or elimination of anxiety in a patient with SAD is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] The reduction or elimination of anxiety 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.

[0666] A clinical response in patients suffering from SAD (including treatment-resistant forms of the disorder) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0667] In patients suffering from SAD (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from SAD (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A 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.

[0668] Remission of anxiety in a patient suffering from such SAD (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

[0669] Relief of anxiety in patients suffering from such SAD (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety in patients suffering from such SAD (including treatment-resistant forms of the disorder), as reflected by a HAM-A score of 7 or less, preferably persists for at least 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.

[0670] A reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0671] The reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 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.

[0672] A reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0673] The reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, preferably persists for at least 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] A reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] The reduction or elimination of anxiety in patients with SAD (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the "Anxiety" item of the BPRS, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, preferably persists for at least 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] Treating patients suffering from SAD (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0677] Reduction or elimination of suicidal ideation in patients with SAD (including treatment-resistant forms of the disorder) is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0678] The reduction or elimination of suicidal ideation in patients with SAD (including treatment-resistant forms of the disorder) occurs within about 2 hours of 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.

[0679] Anxiety is a core feature of panic disorder. Patients with panic disorder experience spontaneous panic attacks, which are sudden onsets of intense fear or discomfort that peak within minutes.

[0680] Panic attacks are characterized by many somatic symptoms of anxiety, including sweating, shaking, trembling, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0681] Additionally, the disorder can often be characterized by anxiety about future panic attacks: patients may become preoccupied with fear of recurrent attacks.

[0682] Patients suffering from panic disorder may suffer from treatment-resistant forms of the disorder.

[0683] The severity of panic disorder can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0684] Panic disorder is also associated with suicidal thoughts.

[0685] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0686] Patients with panic disorder exhibit altered functional connectivity within and / or between the default mode network and the sensorimotor network.

[0687] Treating patients suffering from panic disorder (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0688] The reduction or elimination of anxiety 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] The reduction or elimination of anxiety 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.

[0690] A clinical response in patients suffering from panic disorder (including treatment-resistant forms of the disorder) is reflected by at least a 50% decrease in the HAM-A 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, compared to the respective scores before treatment.

[0691] In patients suffering from panic disorder (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from panic disorder (including treatment-resistant forms of the disorder), a clinical response reflected by at least a 50% reduction in the HAM-A 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.

[0692] Remission of anxiety in a patient suffering from such a panic disorder (including treatment-resistant forms of the disorder) is reflected by a HAM-A score of 7 or less 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.

[0693] Relief of anxiety in patients suffering from such panic disorder (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety in patients suffering from such panic disorder (including treatment-resistant such disorders), as reflected by a HAM-A score of 7 or less, preferably persists for at least 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.

[0694] A reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of such disorders), as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] The reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] A reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of such a disorder), as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0697] The reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the anxious mood section (item 1) of the HAM-A, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0698] A reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of such disorder), as reflected by a decrease in the score for the "Anxiety" item on the BPRS, is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0699] The reduction or elimination of anxiety in patients suffering from panic disorder (including treatment-resistant forms of the disorder), as reflected by a reduction in the score on the "Anxiety" i...

Claims

1. A pharmaceutical composition for treating anxiety in a patient suffering from anxiety, 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 patient also suffers from a mental disorder or a neurological disorder.

3. The pharmaceutical composition according to claim 2, wherein the patient suffering from a mental disorder or neurological disorder also suffers from a treatment-resistant version of the disorder.

4. The pharmaceutical composition according to claim 1, wherein the patient also suffers from a disorder characterized by anxiety-related depressive episodes.

5. The pharmaceutical composition according to claim 4, wherein the patient is currently suffering from a major depressive episode.

6. The pharmaceutical composition according to claim 1, wherein the patient also suffers from anxiety-related depression (MDD).

7. The pharmaceutical composition according to claim 6, wherein the patient, who also suffers from MDD, suffers from the treatment-resistant disorder.

8. The pharmaceutical composition according to claim 1, wherein the aforementioned treatment reduces or eliminates the aforementioned anxiety.

9. The pharmaceutical composition according to claim 8, wherein the reduction or disappearance of the anxiety is observed about two hours after the last dose of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at least one day after the last dose of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof, for example, about 24 hours, at least seven days, at least fourteen days, and / or at least twenty-eight days.

10. The pharmaceutical composition according to claim 2, wherein the treatment results in improvement of the diagnosed disorder in a patient who also suffers from anxiety.

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

12. The pharmaceutical composition according to claim 1, wherein the patient is suffering from suicidal ideation.

13. The pharmaceutical composition according to claim 1, wherein a dose of approximately 4 mg to approximately 20 mg of 5-MeO-DMT is administered, or an equimolar amount of the 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 a 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 each subsequent dose is administered in a larger amount than the previous dose.

17. The pharmaceutical composition according to claim 15, wherein the patient receives subsequent doses unless he or she experiences a peak psychedelic 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 a first dose, then increased to a dose of approximately 8 mg to approximately 14 mg in a second dose, unless the patient has not already experienced a peak psychedelic 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 a third dose, 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 he or she experiences a peak psychedelic experience.

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

21. The pharmaceutical composition according to claim 20, wherein the patient receives a second or third dose unless he or she experiences a peak psychedelic experience.

22. The pharmaceutical composition according to claim 14, wherein the interval between the two administrations is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably 1 to 2 hours.

23. The pharmaceutical composition according to claim 16, wherein the manifestation of a peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales of the 30-item revised Mystical Experiences Questionnaire (MEQ30) (Sacredness, Positive Mood, Transcendence of Space and Time, and Inexpressibility), or by achieving at least 60% of the maximum possible score in the Oceanic Feeling (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 75 in the total score of the Peak Experience Scale (PES).

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 administration, buccal administration, or sublingual administration.

25. The pharmaceutical composition according to claim 1, wherein the anxiety is evaluated using the Hamilton Anxiety Rating Scale (HAM-A).

26. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a salt thereof is administered to the patient in a dose or administration regimen that causes the patient to experience a peak psychedelic experience.