5-Methoxy-N,N-dimethyltryptamine for the treatment of anxiety

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat a patient suffering from anxiety, wherein the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous routes.

Description

[Technical Field]

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

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

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

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

[0005] Anxiety disorders often involve repeated episodes of sudden, intense feelings of anxiety 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 occur in association with medical conditions such as psychiatric disorders or nervous system disorders.In fact, it is known that some psychiatric disorders and nervous system disorders are associated with anxiety.Anxiety also occurs in patients who suffer from certain medical conditions that lead to related mental or nervous system pathologies.

[0008] Anxiety not only has a serious impact on quality of life, but can also cause or exacerbate other mental and physical conditions, such as depression or other mental health disorders, cognitive dysfunction, sleep disorders (e.g., insomnia), substance misuse, digestive or bowel problems, headaches and chronic pain, social isolation, problems functioning in daily life, and suicide, which can be associated with anxiety disorders.

[0009] Current treatment options for anxiety-related conditions are limited.

[0010] Thus, there is a need for improved treatments for such conditions, particularly anxiety related to psychiatric or nervous system disorders, and in patients suffering from certain medical conditions that result in related mental 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 the aforementioned 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 for said therapy that have a superior safety profile and / or are better tolerated than the aforementioned therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapy that are more convenient than the aforementioned therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for said therapy that are associated with higher patient compliance (including higher treatment initiation rates) than the aforementioned therapies. A still further object of the present invention is to identify specific disease states and specific disease subgroups that would benefit from such improved psychoactive therapies.

[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 with an anxiety disorder. The patient may be suffering from an anxiety disorder, a psychiatric or neurological disorder, and subthreshold anxiety, or may have co-morbidities with anxiety and additional diagnosed disorders.

[0014] Anxiety may be a mental or nervous system disorder, 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 / drug-induced anxiety disorders; somatic symptom disorder; 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; and psychological disorders resulting from the use of psychoactive substances. and behavioral disorders, such as 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, and 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 medical health conditions leading to related mental or neurological conditions, such as anxiety due to traumatic brain injury (TBI), HIV infection, or post-COVID conditions.

[0015] Patients may also suffer from anxiety-related sleep disorders.

[0016] The present invention also provides useful dose ranges and regimens for treating anxiety.

[0017] In accordance with the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous administration.

[0018] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in a dosage or regimen that causes the patient to experience a hallucinogenic high. A dosage of about 1 mg to about 10 mg of 5-MeO-DMT, or an equimolar amount of a pharmaceutically acceptable salt, may be administered. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming an equimolar amount is used.

[0020] As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed by a licensed professional in accordance with accepted medical practice with an anxiety disorder, or who is diagnosed by a licensed professional in accordance with accepted medical practice with an anxiety-related psychiatric or nervous system disorder, in which case assessing anxiety may or may not be part of the diagnosis.

[0021] The 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 believe that he or she is suffering from the disorder.

[0022] As used in relation to the present invention, unless otherwise indicated, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of addressing a disease, condition, or disorder, and include the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0023] "Treatment of anxiety" is intended to include the management and care of a patient for the purpose of addressing anxiety, and includes the administration of compounds according to the present invention and methods to alleviate the signs and / or symptoms of anxiety or to eliminate anxiety.

[0024] The patient may suffer from an anxiety disorder or an anxiety-related disorder. Anxiety may be associated with sleep disorders.

[0025] Patient may suffer from treatment-resistant disease.Treatment-resistant means that patient does not show sufficient improvement after at least two appropriate treatment courses.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy, for example, patient does not show sufficient improvement after at least two appropriate drug therapy courses.At least two previous treatment courses are administered, particularly in the current episode of disease, for example, in the current episode of depression, when patient suffers from a disorder characterized by depressive episodes.

[0026] 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 suicidality. Generally, it is not sufficient for the 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."

[0027] As used in connection with this invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician, or other clinician, which biological or clinical response in humans includes alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0028] "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 neurological disorder or aspects of such a disorder.

[0029] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, which is a measure of symptom severity, treatment response, and treatment effectiveness.

[0030] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the clinician's opinion (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0031] The CGI-Severity Scale (CGI-S) is based on a single question that clinicians must answer: "Taking into account your overall clinical experience with this particular population, what is the current level of psychiatric illness in your patient?" This is rated on a 7-point scale: 1 = normal (no illness), 2 = borderline psychiatric illness, 3 = mild illness, 4 = moderate illness, 5 = marked illness, 6 = severe illness, and 7 = very severe illness in patients.

[0032] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0033] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has a similarly brief format. After treatment, clinicians compare the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of project entry (before medication was started), this patient's condition has improved greatly since starting treatment: 1 = very much; 2 = very much; 3 = very minimal; 4 = unchanged from baseline (before treatment was started); 5 = very minimal; 6 = very much worse; 7 = very much worse since treatment was started."

[0034] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is a companion scale to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0035] In addition to the individual items of the scales described herein, subcombinations of the individual items may also be used to assess specific disease aspects.

[0036] As used in connection with the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a predetermined amount of an active compound or pharmaceutical ingredient into a patient by any route. The active compound may be administered intravenously, intramuscularly, or subcutaneously.

[0037] As used in connection with the present invention, unless otherwise specified, the terms "dose" and "administration" and "dosage" shall mean the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined sequence of one or more individual administrations.

[0038] anxiety Anxiety may be defined as "an anxious anticipation of future danger or failure accompanied by physical symptoms of discomfort or tension."

[0039] Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are subjectively viewed as threatening, and is often accompanied by muscle tension, restlessness, fatigue, difficulty breathing, abdominal tightness, nausea, and problems concentrating.

[0040] In anxiety disorders or other anxiety-related mental or nervous system disorders, feelings of anxiety are difficult to control and interfere with daily activities.

[0041] 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 / drug-induced anxiety disorder.

[0042] Anxiety is also associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disorders.

[0043] Measuring anxiety 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 mental and neurological disorders.

[0044] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. It is administered by a clinician. The scale has 14 items, which can be divided into a group of psychological items (items 1-6 and 14) that specifically measure mental agitation and distress, and a group of physical items (items 7-13) that specifically measure physical complaints related to anxiety.

[0045] The HAM-A items are shown in the table below. [Table 1]

[0046] Each item is rated by the interviewer on a scale of 0–4: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

[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 ≤7 is considered to represent no or minimal anxiety, a score of 8–14 mild anxiety, a score of 15–23 moderate anxiety, and a score ≥24 severe anxiety.

[0049] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on somatic 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 means that the patient has a Hamilton Anxiety Rating Scale (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] Scales that may be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, as detailed below.

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

[0054] Evaluations can be performed after the acute hallucinatory experience has subsided. An appropriate time for an initial evaluation is generally about 2-3 hours after the last dose. For example, an initial evaluation can generally be performed about 2 hours or about 3 hours after the last dose.

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

[0056] Thus, evaluation on day 1 or evaluation on day 1 refers to evaluation on the day after dosing. Evaluation will occur no earlier than 12 hours after the last dose, and in any event no earlier than one night after the last dose and no later than 36 hours after the last dose. Evaluation may occur after about 24 hours.

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

[0058] If the clinical response is evaluated at an early time point (for example, 2 hours) after drug administration, for example, using one of the scales for assessing the severity of psychiatric or nervous system disorders, based on the endpoint that is established with a longer recall period (for example, 7 days in MADRS), reasonable modification of such endpoint (for example, changing the recall period of MADRS to 2 hours, and carrying forward the sleep item recorded at the baseline before drug administration) can be applied.Unless the recall period is specifically indicated, the same applies to any other scales applied herein.

[0059] At early time points, the considerations outlined apply because, on the one hand, the influence of the patient's condition before treatment on any scores recorded after treatment to assess clinical response should be kept as low as possible, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[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 the recall period adapted as necessary 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. This scale, one of the most widely used for measuring psychiatric symptoms, 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). Eighteen items (hypochondriasis, anxiety, emotional withdrawal, conceptual integration disorder, guilt, tension, pedantry and unnatural posture, grandiosity, depressed mood, hostility, suspiciousness, hallucinated behavior, decreased movement, uncooperativeness, unnatural thought content, flattened emotions, excitement and disorientation) are scored, and each item is rated on a scale of 1 to 7.

[0062] 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.

[0063] · 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 domain 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. It not only helps identify the immediate need for medical intervention, but also provides 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). 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.

[0066] 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.

[0067] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially specific brain regions that exhibit coordinated activity in the absence of explicit cognitive tasks (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).

[0068] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in working fMRI experiments.

[0069] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0070] RSNs have been shown to be responsible for 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.

[0071] Based on such studies, many brain regions have been linked to anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal 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.

[0072] 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 different anxiety disorders.

[0073] Active Agent The above discussion indicates that anxiety itself poses a significant disease burden and requires appropriate treatment.

[0074] The inventors believed that carefully selected hallucinogens could improve the treatment of important aspects of anxiety and improve the condition overall.

[0075] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families, 5-HT1 through 5-HT7, with several subtypes, have been described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelic drugs" and are primarily characterized by their ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), while other effects such as sedation, narcosis, or hyperstimulation are minimal.

[0076] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines, the latter being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.

[0077] 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.

[0078] Recently published clinical studies using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0079] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a self-reported manic episode after ingesting psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype compared to other classical hallucinogens.

[0084] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0085] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has enhanced affinity for the 5-HT1A receptor and acts as a potent agonist. Psilocin and DMT have an increased contribution to 5-HT2A binding compared to 5-MeO-DMT, with the latter of the three compounds showing the greatest difference between their affinities for 5-HT2A and 5-HT1A. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than the other two compounds.

[0086] 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 is implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0087] 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 neurological disorders, including disorders characterized by depressive episodes (e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD) (such as bipolar I disorder and bipolar II disorder), psychotic disorders, e.g., schizophrenia, or personality disorders, e.g., schizotypal personality disorder). Patients suffering from such psychiatric or neurological disorders, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0088] 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).

[0089] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0090] 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.

[0091] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as a "loss of self"), often leading to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0092] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have demonstrated that 5-MeO-DMT inhibits the 5-HT7 receptor by using 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.

[0093] Thus, in addition to the 5-HT1A and 5-HT2A receptors described above, 5-MeO-DMT also interacts with the 5-HT7 receptor, at which it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the receptor's 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 the receptor.

[0098] 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 with sleep disorders.

[0099] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, in addition to the 5-HT1A receptor, as two mediators of the effects of 5-MeO-DMT, including "resetting" functional network connectivity and neuroplasticity, may also enable it to exert beneficial effects in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0100] Another characteristic of 5-MeO-DMT is its short half-life.

[0101] 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.

[0102] 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.

[0103] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, and 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. Titrating doses as disclosed herein does not result in accumulation, and thus does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0104] The properties of 5-MeO-DMT make the compound particularly suitable for the treatment of anxiety in patients suffering from a psychiatric or neurological disorder, or a medical condition leading to a related psychiatric or neurological pathology, in patients suffering from a sleep disorder, e.g., insomnia, and in patients suffering from an unspecified neurocognitive disorder.

[0105] The properties of 5-MeO-DMT also allow for specific dosing regimens, as described in more detail below.

[0106] 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.

[0107] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0108] 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.

[0109] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced into one or more defined hydrogen positions.

[0110] 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.

[0111] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group. Further examples include 5-MeO-DMT forms in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0112] Methods for preparing these compounds are known in the art.

[0113] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0114] 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.

[0115] 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.

[0116] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0117] 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.

[0118] 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.

[0119] Prodrugs (especially those with the above structure) can also be used in the form of pharmaceutically acceptable salts.

[0120] 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).

[0121] Methods for preparing the prodrugs described herein are known in the art.

[0122] 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.

[0123] 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.

[0124] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenously, i.e., by intravenous injection.

[0125] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection; examples of excipients and vehicles for such formulations are known in the art.

[0126] Dosage regimen The present invention also provides dose ranges, specific doses, and administration regimens (administration schemes), and suitable routes of administration.

[0127] The present invention is based in part on the inventors' conclusion that the occurrence of an acute hallucinogenic peak experience following administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof causally facilitates, or at least serves as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from anxiety, particularly one or more of the aspects defined above.

[0128] The result is a superior therapeutic profile, achieving peak experiences more rapidly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens, dosing regimens, and routes of administration.

[0129] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no attenuation or disappearance of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily) designed to increase the incidence of peak experiences and thereby enhance therapeutic efficacy. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time), induction of mania or hypomania, or a meaningless hallucinogenic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at that higher dose. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the treatment approach and improve overall compliance at the patient population level.

[0130] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate and modulate the reproducibility of peak experiences, and to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other hallucinogens due to the slow onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration), which may last for several days.

[0131] A patient as defined herein suffering from an anxiety disorder is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0132] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy (ie, the patient is not receiving any other treatment for anxiety).

[0133] The dosage of 5-MeO-DMT defined herein for administration to a patient suffering from anxiety disorders ranges from about 1 mg to about 10 mg, or any amount within that range, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated from the stated weight of 5-MeO-DMT free base, assuming equimolar amounts are used. Useful specific amounts of 5-MeO-DMT include, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. It should be noted that when a range such as "about 1 mg to about 10 mg" is 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).

[0134] In a preferred embodiment, the improved method for treating a patient suffering from an anxiety disorder, as defined herein, with a therapeutically effective amount of 5-MeO-DMT comprises generating a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0135] In a preferred embodiment, the improved method for treating a patient as defined herein suffering from an anxiety disorder with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, comprising a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT, for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0136] In a preferred embodiment, the improved method for treating a patient suffering from an anxiety disorder as defined herein with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0137] 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 with the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0138] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 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.

[0139] In a most preferred embodiment, the patient is administered more than one dose of 5-MeO-DMT 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.

[0140] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0141] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0142] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0143] For embodiments in which the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration will be 7 mg.

[0144] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first treatment, and then increased to a dose selected from about 4 mg to about 6 mg for the second treatment, and to a dose selected from about 7 mg to about 9 mg for the third treatment, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third treatments are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0145] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first treatment, and then increased to a dose selected from about 1.5 mg to about 2.5 mg for the second treatment and to a dose selected from about 2.5 mg to about 3.5 mg for the third treatment, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third treatments are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0146] In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration in a first treatment block, and then increased for each subsequent administration in the first treatment block until it reaches 10 mg or all administrations in that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic peak experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dose in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a hallucinogenic peak experience at a dose of 8 mg, and therefore the highest dose in the first treatment block was 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 8 mg.

[0147] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0148] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0149] A pharmaceutically acceptable salt of 5-MeO-DMT is preferably used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0150] According to the present invention, it is preferred that 5-MeO-DMT not be administered in conjunction with an MAO inhibitor.

[0151] The occurrence of a "psychedelic peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0152] The occurrence of a "psychedelic peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0153] In accordance with the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also known as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience?; 2. How out of control was it?; and 3. How profound (i.e., meaningful) was the experience?

[0154] Treating anxiety The present invention can treat anxiety in patients suffering from an anxiety disorder or other anxiety-related psychiatric or neurological disorder, and can also treat anxiety in patients suffering from sleep disorders, such as insomnia.

[0155] 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 anxiety-related conditions.

[0156] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0157] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption allows pathological maladaptive connections to be reset as networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0158] Thus, in accordance with the present invention, affecting these networks via the treatments described herein will result in an improvement in anxiety, and 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, the sleep disorder, e.g., insomnia, will also be improved.

[0159] To further support the clinical application of 5-MeO-DMT in patients suffering from anxiety disorders, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders, noting the specific improvement in anxiety that is also commonly seen in patients with other disorders.

[0160] 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 may be relevant for devising treatments for anxiety disorders and other anxiety-related conditions, as detailed below.

[0161] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to various groups. Of interest in the context of the present invention are those receiving a single 12 mg dose and those receiving an intra-day individualized dosing regimen (IDR), which allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0162] 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 the study was to demonstrate treatment efficacy through improvement in overall MADRS scores, the inventors looked at the items that make up the various scales, noting that specific subscore items, such as those related to anxiety, may also be relevant to other conditions in which anxiety is based on similarly altered functional connectivity within and / or between resting-state networks.

[0163] Multiple patients within the pooled cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0164] More particularly, an aspect that can be treated by administering 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to a patient to reduce or eliminate anxiety in said patient.

[0165] A particularly relevant BPRS item in this regard is "Anxiety." This item concerns reported apprehension, tension, fear, panic, or worry. Possible scores are as follows:

[0166] 1 - No anxiety.

[0167] 2 - Very mild. Reports discomfort due to worry that occurs more frequently than most healthy people or occasional worry.

[0168] 3 - Mild. Frequent worry, but able to quickly shift attention elsewhere.

[0169] 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.

[0170] 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety, or some areas of functioning are impaired by anxiety or worry.

[0171] 6 - Severe. Autonomic anxiety occurs daily but not all day long, or many areas of functioning are impaired by anxiety and constant worry.

[0172] 7 - Most severe. Autonomic anxiety is present throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0173] The aggregated BPRS "anxiety" item score across all eight patients in the study group receiving the individualized dosing regimen was 37 at baseline.

[0174] 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.

[0175] Aggregate BPRS "anxiety" item scores across all four patients in the 12 mg group had a baseline of 25.

[0176] 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.

[0177] The inventors conclude that 5-MeO-DMT may be used to treat anxiety in patients, including those suffering from anxiety disorders and those suffering from psychiatric or nervous system disorders with associated anxiety.

[0178] 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.

[0179] The MADRS item "Internal Tension" describes an increase in mental tension towards either undefined discomfort, anxious feelings, inner turmoil, panic, fear, or distress, which is graded according to intensity, frequency, duration, and the degree of stability desired.

[0180] If the patient is calm and has only momentary inner tension, a score of 0 is assigned. If there are occasional feelings of anxiety, undefined discomfort, a score of 2 is assigned. If there is continuous inner tension or intermittent panic that the patient can overcome with only some difficulty, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

[0181] In the TRD patient study described above, the aggregated MADRS "internal tension" item score across all eight patients in the study group receiving the individualized dosing regimen was 26 at baseline. 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.

[0182] In the 12 mg group, the aggregated scores for the "internal tension" item on the MADRS across all four patients were 13 at baseline. After 2 hours, the score had decreased to 2, corresponding to an 11-point or 85% improvement. On the first day after treatment, the score had decreased to 3, corresponding to a 10-point or 77% improvement. On the seventh day after treatment, the score had decreased to 5, corresponding to an 8-point or 62% improvement.

[0183] These results further support the inventor's conclusion that treatment according to the present invention reduces or eliminates symptoms of anxiety.

[0184] Treatment according to the present invention results in a clinical response in patients suffering from anxiety symptoms as reflected by at least a 50% reduction in the HAM-A score compared to the scores before treatment, about 2 hours, 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.

[0185] The clinical response in a patient suffering from anxiety, as reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in a patient suffering from anxiety, as 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.

[0186] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms is reflected by a HAM-A score of 7 or less at about 2 hours, 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.

[0187] In a patient suffering from anxiety symptoms, remission of anxiety symptoms, as reflected by a HAM-A score of 7 or less, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In a patient suffering from anxiety symptoms, remission of 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.

[0188] 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.

[0189] Anxiety and sleep A sleep disorder refers to a medical condition that affects the quality, timing, or duration of sleep and is idiopathic or occurs in association with a medical condition, such as a psychiatric or neurological disorder, or that results in an associated mental or neurological condition, which affects a person's ability to function properly during wakefulness, particularly impairing cognitive function and causing anxiety.

[0190] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be categorized into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, non-REM sleep is deeper and occupies a disproportionate amount of time, especially within the first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle being allocated to REM sleep.

[0191] Normal, healthy sleep consists of different phases, as outlined above, that proceed sequentially and in a tightly regulated order throughout the night.

[0192] Disruption of this tight regulation results in sleep disorders.

[0193] 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 partial awakenings (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0194] Insomnia is a sleep disorder that makes it difficult for people to fall asleep or to stay asleep. People with insomnia have difficulty falling asleep, frequent awakenings during the night, difficulty returning to sleep, waking up too early in the morning, unrefreshing sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood problems, concentration problems, or accidents at work or while driving.

[0195] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep intoxication is also a symptom observed in patients with hypersomnia. The transition from sleep to wakefulness is difficult. Individuals experiencing sleep intoxication report awakenings with confusion, disorientation, sluggishness, and repeated cycles of returning to sleep.

[0196] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances resulting from alterations in an individual's internal rhythms or from a mismatch between circadian rhythms and desired or required work or social schedules. This dyssynchronization can be transient or persistent. The resulting clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during desired wakefulness is impaired, and temporary opportunities to return to a normal sleep schedule are unsuccessful.

[0197] Parasomnia refers to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) that people experience before falling asleep, during sleep, or during periods of wakefulness between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnia can impair sleep quality.

[0198] Sleep-related breathing disorders are characterized by abnormal difficulty breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of the respiratory muscles and the brain (control center). One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals that control breathing, for example, based on an underlying health condition. 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.

[0199] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements disrupt sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0200] 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.

[0201] Sleep disorders such as insomnia have a high comorbidity rate with anxiety disorders. Insomnia often precedes the onset of anxiety, so insomnia and anxiety may be mutually influential conditions. 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.

[0202] Anxiety affects the sleep cycle, and anxiety and pre-sleep rumination affect rapid eye movement (REM) sleep, which involves the most vivid dreaming, often inducing more disturbing dreams and therefore a greater likelihood of disrupted sleep.

[0203] Furthermore, the difficulty of falling asleep itself can create sleep anxiety, which compounds the problem and reinforces a person's fears and preoccupations. These negative thoughts about going to bed, a form of anticipatory anxiety, can create challenges to healthy sleep schedules and routines.

[0204] Lack of sleep can worsen anxiety and contribute to the negative cycle of insomnia and anxiety.

[0205] 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.

[0206] Poor sleep has a significant impact on functional impairment: patients with anxiety disorders and sleep disorders experience significantly reduced mental health-related quality of life and increased disability compared to patients with anxiety disorders alone.

[0207] Because of the bidirectional relationship between sleep disorders (mainly insomnia) and anxiety, sleep disorders are very common in patients with social anxiety disorder, agoraphobia, phobias, and substance / drug-induced anxiety disorders.

[0208] 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 or staying asleep, early awakenings, and parasomnias.

[0209] In the case of generalized anxiety disorder, sleep disturbances, particularly difficulty falling asleep or staying asleep, or restless, unsatisfying 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, of which at least three must be present over a period of time, to meet the diagnosis of GAD.

[0210] 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 make it difficult to fall asleep again.

[0211] 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, medication or psychological therapy may also be included.

[0212] 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.

[0213] In patients suffering from a sleep disorder associated with a psychiatric or nervous system disorder, known treatments for the psychiatric or nervous system disorder do not necessarily improve the sleep disorder.

[0214] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treatment of depression does not necessarily result in improvement of the associated sleep disorders. Most antidepressants have been shown to affect sleep architecture, and while some classes of antidepressants improve sleep, others may cause sleep disorders.

[0215] To assess sleep, parameters such as sleep duration, sleep architecture, sleep latency, and frequency and duration of wakefulness throughout the night can be measured. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-report measures (questionnaires).

[0216] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic to measure a variety of functions throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0217] Another quantitative measure is actigraphy, in which actimetric sensors are worn to measure motor activity, which is then 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.

[0218] 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, while less than 8 minutes indicates a sleep disorder / excessive daytime sleepiness. Analysis of accompanying brain activity can aid in further diagnosis of sleep disorders.

[0219] Sleep assessment questionnaires collect assessments of components of sleep quality, such as perceived depth of sleep, difficulty waking, and restfulness after sleep, as well as assessments of other factors that may affect sleep quality, such as comorbidities and medication use. Anxiety and sleep disorders are linked, so anxiety can be part of the assessment.

[0220] Assessment of qualitative aspects of the sleep experience is important because, in many cases, sleep discomfort can persist despite normality of quantitative measures of sleep.

[0221] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but are also potentially 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.

[0222] 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 indices or questionnaires.

[0223] Some questionnaires rely on a recall period (recall window) of several days or weeks. This may be appropriate for diagnosing sleep disorders, but it is not always appropriate for evaluating the rapid onset of treatment effect, especially the effect after treatment. For some questionnaires, the recall period can be modified so that the score obtained reflects the period after treatment. The questionnaires specifically described herein for evaluating the effect of treatment on the sleep of patients suffering from certain pathologies rely on a recall period that does not start earlier than the time when acute hallucinatory experience subsides after the last administration. To meet this criterion, the recall period that is usually applied is modified as necessary.

[0224] Sleep quality can generally be assessed, for example, with the Sleep Quality Scale (SQS) and the Sleep-50 questionnaire.

[0225] 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, or memory problems (item 15: "Because of lack of sleep, I have difficulty thinking," item 19: "Because of lack of sleep, I make mistakes at work," item 21: "Because of lack of sleep, I tend to forget things," and item 22: "Because of lack of sleep, I have difficulty concentrating on work"), recovery after sleep, problems initiating and maintaining sleep, and difficulty waking, as well as sleep satisfaction, can be scored from 0 ("rarely") to 3 ("almost always"), with higher scores indicating more acute sleep problems (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). Respondents are asked to report their experiences during the previous month or another appropriate recall period.

[0226] Successful treatment is indicated by a decrease in score.

[0227] The SLEEP-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. This scale consists of nine subscales that reflect the most common sleep-related disorders and disorders, as well as diagnostic factors for sleep apnea, insomnia, narcolepsy, restless legs / periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, and 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 much") and asked to indicate how well the answer matches their experience over the past month or another appropriate recall window.

[0228] To diagnose a sleep disorder, not only must certain subscales (e.g., insomnia) be above certain cutoff points, but respondents must also meet a cutoff of at least 3 or 4 ("quite a bit" or "very much") on the subscale assessing the impact of sleep disturbance on daily functioning (Spoormaker et al. Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0229] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0230] 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.

[0231] 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.

[0232] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) chronic sleep efficiency, (5) sleep disturbances, (6) use of sleeping medications, and (7) daytime functioning disorders.

[0233] 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.

[0234] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. The cutoff for the overall score is 5, which distinguishes between individuals with and without sleep problems. A overall score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0235] 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.

[0236] The Insomnia Severity Index (ISI) is a short questionnaire that assesses subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning (item 3, "To what extent do you think your sleep disturbances affect your daily functioning (e.g., daytime fatigue, ability to perform work / daily chores, concentration, memory, mood)?"), how significant the respondent perceives their insomnia compared to others, and the overall level of distress caused by sleep disturbances. Individual responses can be scored from 0 (none) to 4 (very), with higher total scores corresponding to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 means "subthreshold insomnia," 15–21 means "moderate clinical insomnia," and 22–28 means "severe clinical insomnia" (A. Shahid et al., loc.cit.). The typical recall window for ISI is two weeks, although other suitable recall windows may be used herein.

[0237] Successful treatment is indicated by (i) a reduction in score, for example above 7, especially above 8, and preferably (ii) a reduction below the cut-off for clinically significant insomnia.

[0238] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. Following assessments of restlessness / irritability, mental hyperactivity, consequences of insomnia, and lack of readiness to fall asleep, the SDQ specifically focuses on beliefs about the causes of sleep disturbances. Respondents use a 5-point scale to indicate how frequently specific references to insomnia represent 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.;).

[0239] Successful treatment is indicated by a decrease in score.

[0240] The Patient-Reported Outcomes Information System (PROMIS®) Sleep Disorders Instrument is a universal measure for assessing sleep disorders. This instrument is available in a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reports of sleep quality, sleep depth, and any perceived difficulty with falling asleep and staying asleep over a 7-day period.

[0241] Each item on the measure is rated on a 5-point scale. The item raw scores are summed to obtain a total score. The total score is then converted to a standardized T-score using a conversion table.

[0242] Successful treatment is indicated by a decrease in T-score.

[0243] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Rating Scale.

[0244] 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 stopped in traffic. Using a scale of 0 to 3 (0 meaning "I will never fall asleep" and 3 meaning "I will likely fall asleep"), respondents rate their likelihood of falling asleep. Scoring ranges from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., loc.cit.).

[0245] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0246] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment. This single-item scale requires respondents to select one of seven statements that best describes their current level of sleepiness. Levels of sleepiness are assessed using a scale ranging from 1 (= active and energetic, alert, wide alert) to 7 (= mostly sleepy, falls asleep easily, has trouble staying awake) (A. Shahid et al., loc.cit.).

[0247] Successful treatment is indicated by a decrease in score.

[0248] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0249] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnia behaviors, rates 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).

[0250] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0251] 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.

[0252] Successful treatment is indicated by a decrease in score.

[0253] A common questionnaire assessing sleep-related movement disorders is the International Restless Legs Syndrome Severity Scale. The 10-item questionnaire asks respondents to indicate how acutely the disorder has affected them 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 disturbances, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their RLS experience on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least severe symptoms. Total scores can range from 0 to 40. Because this instrument is a brief scale with excellent psychometric properties, it may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes. (A. Shahid et al., loc.cit.)

[0254] Treatment response can be assessed by a reduction in score.

[0255] Treatment response can be assessed by the use of the above-mentioned quantitative measurements, such as polysomnography or actigraphy, and / or the above-mentioned questionnaires. Depending on the respective sleep scale, a significant decrease or increase in the total score, or a significant decrease in the prevalence, frequency, and impact on daily function, respectively, indicates treatment-induced improvement of the sleep disorder.

[0256] 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, waking during the night, unsatisfactory sleep, and fatigue, dreams, nightmares, and night terrors upon awakening." Each item is scored on a scale from 0 (absent) to 4 (severe).

[0257] Resting-state fMRI has been widely applied in patients with sleep disorders to better understand the pathophysiology and potential compensatory mechanisms.

[0258] Alterations in the resting-state network can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0259] In patients with insomnia, dysfunctional connectivity has been observed within the default mode network (DMN) and the salience network, which are involved in the detection and integration of emotional and sensory stimuli. Research has shown that these networks contain important regions that integrate emotional and physical states, and dysfunctional connectivity within these networks and / or between these networks and other brain regions may underlie patients' arousal, subjective distress, and reduced sleep continuity.

[0260] For example, sleep disruption 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.

[0261] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, different DMN hubs, the prefrontal cortex and medial prefrontal cortex, show significant alterations, and DMN functional connectivity correlates with the severity of self-reported sleepiness.

[0262] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm irregularities contribute to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as reactivity and alertness. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders can lead to alterations in functional brain connectivity. Alterations in functional brain connectivity during rest have been reported in various disorders associated with circadian rhythm disorders.

[0263] 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 parasomnias.

[0264] The precuneus is involved in analyzing and integrating visual, auditory, and sensory information, and in monitoring movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnia, the default mode network is affected.

[0265] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, have shown significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems. Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Activity in the cerebellum and thalamus can also be observed, with additional activation in the red nucleus and brainstem.

[0266] Resting-state networks involved in sleep regulation are often also involved in cognition, and thus, in accordance with the present invention, affecting these networks through treatment in accordance with the present invention results in improvement of sleep disorders and, if the treated patient suffers from an anxiety disorder, also in improvement of anxiety.

[0267] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that sleep disorders can be effectively treated by administration of 5-MeO-DMT.

[0268] The TRD study, described in more detail in the Examples section below, specifically assessed the MADRS item "Decreased Sleep," which reflects insomnia.

[0269] The "Decreased Sleep" item on the MADRS refers to the experience of decreased duration or depth of sleep compared to the subject's normal pattern when healthy. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, shallow, or disrupted sleep. A score of 4 means at least 2 hours of reduced or disrupted sleep. A score of 6 means less than 2 or 3 hours of sleep.

[0270] Aggregate scores on the MADRS "Decreased Sleep" item across all eight patients in the study group receiving the individualized dosing plan 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.

[0271] The combined MADRS "Decreased Sleep" item scores across all four patients in the 12 mg group had a baseline of 12. On day 1 after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. On day 7 after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0272] Thus, scores on the scale item "decreased sleep," which is particularly relevant to sleep disorders, are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat patients suffering from sleep disorders, particularly psychiatric or nervous system disorders.

[0273] Treating patients suffering from sleep disorders, particularly insomnia, and associated anxiety disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the sleep disorder, particularly insomnia.

[0274] The reduction or elimination of anxiety in patients suffering from a sleep disorder, particularly insomnia, is observed at about 2 hours, 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.

[0275] 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.

[0276] 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.In addition, 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.

[0277] In the case of idiopathic sleep disorders, clinical response can be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least one level. Preferably, the CGI-S score is decreased by at least two levels and / or to a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three levels and / or to a score of 0.

[0278] Improvement in the idiopathic sleep disorder, as reflected by a reduction in the 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.

[0279] Improvement in the idiopathic sleep disorder, as reflected by a decrease in CGI-S score, occurs by about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0280] The improvement in the idiopathic sleep disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0281] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0282] In the case of idiopathic sleep disorders, improvement in the sleep disorder, as reflected by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0283] Improvement in sleep disorders may also be assessed by any other measure that reflects changes in quality or quantity of sleep as described above, for example, the Pittsburgh Sleep Quality Index (PSQI).

[0284] 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.

[0285] Improvement in sleep disturbance is reflected by a decrease in PSQI score, particularly a decrease to 5 or less, and preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period begins no earlier than the time the acute hallucinatory experience has subsided between the last administration and the time of assessment.

[0286] The improvement in sleep disturbance, as reflected by a reduction in PSQI score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, wherein the recall period does not begin any earlier than the time the acute hallucinatory experience between the last administration and the time of assessment has subsided.

[0287] Improvement in sleep disturbance, reflected as a decrease in PSQI score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, where the recall period begins no earlier than the time the acute hallucinatory experience has subsided between the last administration and the time of assessment.

[0288] Anxiety and sleep disorders, especially insomnia, are closely related to mental and nervous system disorders.Anxiety and sleep disorders, especially insomnia, are closely related to disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder and bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder and phobia; and substance / drug-induced anxiety disorder; somatic symptom disorder, obsessive-compulsive and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); somatoform disorders, such as body dysmorphic disorder (BDD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), pain disorders; For example, it occurs in chronic pain, and mental or nervous system disorders such as fibromyalgia and migraine, mental and behavioral disorders resulting from the use of psychoactive substances, e.g., substance use disorders (SUD), psychotic disorders, e.g., schizophrenia, Parkinson's disease, or schizotypal personality disorder, dementia, e.g., Alzheimer's disease (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia, Parkinson's disease (PD), eating disorders, attention deficit hyperactivity disorder (ADHD), personality disorders, e.g., schizotypal personality disorder and borderline personality disorder, autism spectrum disorder, and chronic fatigue syndrome.

[0289] Anxiety and sleep disorders, particularly insomnia, both occur in medical health conditions that result in associated mental or neurological pathologies, such as HIV, traumatic brain injury, or post-COVID conditions.

[0290] Treatment according to the present invention improves both anxiety and sleep disorders, particularly insomnia, as well as related psychiatric or neurological disorders (examples of which are listed above), and, as explained above, also improves psychiatric or neurological pathologies associated with certain medical conditions.

[0291] Treatment of anxiety and other mental and nervous system disorders Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0292] A depressive episode is a period of depressed mood and / or loss of enjoyment in most activities.

[0293] 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, with at least one of the symptoms being either (1) depressed mood or (2) loss of interest or enjoyment.

[0294] Patients suffering from a disorder characterized by depressive episodes may be suffering from a treatment-resistant form of the disorder.

[0295] Patients suffering from a disorder characterized by depressive episodes may additionally exhibit symptoms of anxiety, although they have not been diagnosed with an anxiety disorder (subthreshold anxiety).

[0296] As used herein, the term "subthreshold anxiety" specifically means that the patient has a Hamilton Anxiety Rating Scale (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.

[0297] A patient may also be diagnosed with a disorder characterized by depressive episodes and may also be diagnosed with an anxiety disorder, i.e., may be considered to have comorbid disorders and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0298] Anxiety symptoms in patients with disorders characterized by depressive episodes, such as those with the disorder and subthreshold anxiety, or those with comorbid disorders and anxiety, are associated with greater depression severity and increased incidence of suicidal ideation.

[0299] Anxiety in patients suffering from a disorder characterized by depressive episodes may 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 (global), 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."

[0300] Suicidal ideation may be assessed using the "suicidal thoughts" item on the MADRS or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0301] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity within and / or between several brain regions involved in processing, regulation, emotional memory, cognitive processes related to rumination, lack of concentration, and physiological arousal are observed.Anxiety is also associated with abnormal connectivity within and / or between resting-state networks such as the default mode network and the salience network.Abnormal connectivity can be normalized by treatment according to the present invention.

[0302] Treating patients with a disorder, including treatment-resistant forms of the disorder, characterized by depressive episodes and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the disorder.

[0303] Reduction or elimination of anxiety in patients suffering from a disorder, including a treatment-resistant form of the disorder, characterized by a depressive episode, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, is observed at about 2 hours, 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.

[0304] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients who have both the disorder and 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.

[0305] In patients suffering from a disorder, including a treatment-resistant form of the disorder, characterized by a depressive episode and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 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.

[0306] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease 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.

[0307] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, 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 at about 2 hours, 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.

[0308] In patients suffering from a disorder, including a treatment-resistant form of disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0309] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0310] In patients suffering from a disorder, including a treatment-resistant form of a disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, 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, 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, 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.

[0311] In patients suffering from a disorder, including a treatment-resistant form of the disorder, characterized by a depressive episode, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0312] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0313] In patients suffering from a disorder, including a treatment-resistant form of the disorder, characterized by depressive episodes and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "mental anxiety" and / or "somatic anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0314] In patients suffering from a disorder, including a treatment-resistant form of a disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from both the disorder and an anxiety disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0315] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, is observed at about 2 hours, 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.

[0316] In patients suffering from a disorder, including a treatment-resistant form of disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "internal tension" item of the MADRS, 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0317] In patients suffering from a disorder, including a treatment-resistant form of the disorder characterized by a depressive episode, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0318] In patients suffering from a disorder, including a treatment-resistant form of disorder characterized by depressive episodes, and who have anxiety symptoms, e.g., patients suffering from both the disorder and subthreshold anxiety, or patients suffering from a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0319] A clinical response in patients suffering from a disorder characterized by depressive episodes 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0320] A clinical response in patients with 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 of 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.

[0321] In patients suffering from a disorder characterized by depressive episodes and subthreshold anxiety, the clinical response, 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.

[0322] A clinical response in patients with a disorder characterized by a depressive episode and a comorbid anxiety disorder 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0323] The clinical response in patients with a disorder characterized by a depressive episode and a comorbid anxiety disorder, 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 after 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-D score and at least a 50% reduction in the HAM-A score in patients with a disorder characterized by a depressive episode and a comorbid anxiety disorder, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0324] Remission in patients suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, and subthreshold anxiety, or patients with comorbid anxiety and a treatment-resistant form of the 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0325] In patients suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a treatment-resistant form of the disorder, remission 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 after 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 persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0326] Treatment of patients with a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, and subthreshold anxiety, or patients with comorbid anxiety and this disorder, including treatment-resistant forms, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof, reduces or eliminates suicidal ideation.

[0327] In patients suffering from a disorder characterized by depressive episodes, including a treatment-resistant form of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a treatment-resistant form of the disorder, a reduction or resolution of suicidal ideation, as reflected by a decrease in the score on the "Suicidal Thoughts" item of the MADRS, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 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 forms of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a treatment-resistant form of the disorder, the reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, preferably persists for at least 6 days, particularly at 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] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. Depression affects a person's emotions, thoughts, and behavior and can cause a variety of emotional and physical problems.

[0330] Patients suffering from MDD may have a treatment-resistant form of the disorder.

[0331] Patients with MDD may also exhibit symptoms of anxiety, although they have not been diagnosed with an anxiety disorder (subthreshold anxiety). As this term is used herein, such patients suffer from anxiety depression.

[0332] As used herein, the term "subthreshold anxiety" specifically means that the patient has a Hamilton Anxiety Rating Scale (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.

[0333] A patient may also be diagnosed with MDD and further diagnosed with an anxiety disorder, i.e., may be considered to have comorbid anxiety and depression (as opposed to anxiety-depression). Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0334] Anxiety symptoms in patients with MDD, including those with anxiety depression or those with comorbid anxiety and depression, are linked to more severe depression and increased incidence of suicidal ideation.

[0335] Anxiety in patients with MDD may 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 (global), 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."

[0336] Suicidal ideation may be assessed using the "suicidal thoughts" item on the MADRS or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0337] In patients with MDD, dysfunction is observed in the connections and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. 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. Abnormal connectivity can be normalized by treatment according to the present invention.

[0338] Treating patients with MDD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients who have anxious depression or who have comorbid anxiety and MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement in MDD.

[0339] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have an anxious depression, or patients who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety is observed at about 2 hours, 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.

[0340] In patients with MDD, including treatment-resistant forms of the disorder, who have anxiety symptoms, such as anxiety-depression, or who have a comorbid anxiety disorder and MDD, 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.

[0341] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have an anxious depression, or patients who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 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.

[0342] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, such as patients with anxiety-related depression or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease 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.

[0343] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, a reduction or elimination of anxiety, 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 at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0344] In patients with MDD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxiety-depressive disorder, or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0345] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have anxious depression or who have comorbid anxiety and MDD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0346] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, 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, 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, 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.

[0347] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have an anxious depression, or patients who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0348] In patients with MDD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxiety-depressive disorder, or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0349] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have anxious depression or who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0350] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0351] In patients with MDD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients who have an anxious depression or who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, is observed at about 2 hours, 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] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, 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, as reflected by a decrease in the score on the "inner tension" item of the MADRS, preferably persists for at least 6 days, particularly at 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] In patients with MDD, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have an anxious depression or who have a comorbid anxiety disorder and MDD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0354] In patients with MDD, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and MDD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0355] 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0356] The clinical response in a patient suffering from anxiety and depression, 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in a patient suffering from anxiety and depression, 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.

[0357] A 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0358] The clinical response in patients with comorbid anxiety and MDD, 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 pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients with comorbid anxiety and MDD, 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.

[0359] Remission of anxiety depression or comorbid anxiety and MDD in patients suffering from such disorders, including treatment-resistant forms of the 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0360] Remission of anxiety depression or comorbid anxiety and MDD in patients suffering from such disorders, including treatment-resistant forms of the disorders, 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety depression or comorbid anxiety and MDD in patients suffering from such disorders, including treatment-resistant forms of the disorders, as reflected by a HAM-A score of 7 or less and a HAM-D 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.

[0361] Treating patients with MDD, including treatment-resistant forms of the disorder, who also have anxiety symptoms, e.g., patients who have an anxious depression or who have comorbid anxiety and MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0362] A reduction or elimination of suicidal ideation in patients suffering from anxiety-depression or comorbid anxiety disorder and MDD, including treatment-resistant forms of the disorder, as reflected by a reduction in the score on the MADRS item "Suicidal Thinking," is observed at about 2 hours, 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.

[0363] The reduction or elimination of suicidal ideation in patients suffering from an anxious depression or comorbid anxiety disorder and MDD, including treatment-resistant forms of the disorder, as reflected by a reduction in the score on the MADRS item "Suicidal Thoughts," occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of suicidal ideation in patients suffering from an anxious depression or comorbid anxiety disorder and MDD, including treatment-resistant forms of the disorder, 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.

[0364] Postpartum depression (PPD) is a debilitating mood disorder that occurs during pregnancy or within four weeks of giving birth. While over 50% of women experience temporary low mood and tearfulness after giving birth, some women develop PPD. Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0365] 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 Rating Scale for Depression (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 Rating Scale for Depression (HAM-D) score of 27 or greater.

[0366] 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 Rating Scale for Depression (HAM-D) score of 16 or greater.

[0367] 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.

[0368] Additionally, 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.

[0369] Patients with PPD may have a treatment-resistant form of the disorder.

[0370] Anxiety symptoms are a key feature of PPD. They are significantly more common in women who experience postpartum depression than in women who do not.

[0371] It is believed that the additional burden of anxiety symptoms may result from the responsibilities of caring for a newborn and significant sleep deprivation.

[0372] Both depression and anxiety during the postpartum period not only affect the mother's overall health, but also the way she interacts with her child and, therefore, the child's development.

[0373] PPD can be assessed by the Edinburgh Postnatal Depression Scale (EPDS), which assesses how the mother has felt over the past seven days. Anxiety is assessed in three of the ten questions assessed in the questionnaire. Ratings range 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.

[0374] Patients with PPD exhibit significant alterations in neural activity in brain regions important for self-regulation, empathy, and cognition. PPD is associated with dysfunctional resting-state network connectivity, e.g., between and / or within the default mode network and the frontoparietal control network.

[0375] Anxiety is also associated with abnormal connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which may be normalized by treatment according to the present invention.

[0376] Treating patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients who have anxious depression or who have comorbid anxiety and PPD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of PPD.

[0377] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients who have an anxious depression, or patients who have a comorbid anxiety disorder and PPD, a reduction or elimination of anxiety is observed at about 2 hours, 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.

[0378] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, such as anxiety-depression, or who have a comorbid anxiety disorder and PPD, 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.

[0379] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0380] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, such as anxiety-depression, or who have a comorbid anxiety disorder and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease 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.

[0381] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, 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 at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0382] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxiety-depression, or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0383] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0384] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, 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, 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, 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.

[0385] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0386] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0387] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0388] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0389] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, is observed at about 2 hours, 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.

[0390] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "internal tension" item of the MADRS, 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0391] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression or patients with comorbid anxiety and PPD, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0392] In patients with PPD, including treatment-resistant forms of the disorder, who have anxiety symptoms, e.g., patients with anxious depression, or patients with comorbid anxiety and PPD, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0393] 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0394] The clinical response in a patient suffering from anxiety and depression, 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in a patient suffering from anxiety and depression, 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.

[0395] A 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0396] The clinical response in 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 pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in 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.

[0397] Remission of anxiety-depression or comorbid anxiety and PPD in patients suffering from such disorders, including treatment-resistant forms of the 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0398] Remission of anxiety depression or comorbid anxiety disorder and PPD in patients suffering from such disorders, including treatment-resistant forms of the disorders, 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety depression or comorbid anxiety disorder and PPD in patients suffering from such disorders, including treatment-resistant forms of the disorders, as reflected by a HAM-A score of 7 or less and a HAM-D 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.

[0399] Treating patients with PPD, including treatment-resistant forms of the disorder, who also have anxiety symptoms, e.g., patients with anxious depression or who have comorbid anxiety and PPD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0400] In patients suffering from comorbid anxiety depression or anxiety disorder and PPD, including treatment-resistant forms of the disorder, reduction or resolution of suicidal ideation, as reflected by a decrease in the score on the MADRS item "Suicidal Thoughts," is observed at about 2 hours, 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.

[0401] The reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS in patients suffering from comorbid anxiety-depression or anxiety disorders and PPD, including treatment-resistant forms of the disorders, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS in patients suffering from comorbid anxiety-depression or anxiety disorders and PPD, including treatment-resistant forms of the disorders, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0402] Anxiety further impairs maternal function.

[0403] Maternal functioning can be assessed, for example, using the Barkin Index of Maternal Functioning (BIMF). This index was designed to measure functioning during the year following childbirth. The BIMF is a 20-item self-report functioning scale. Each item is assigned a score of 0 to 6, with a maximum total score of 120. A higher score indicates better maternal functioning.

[0404] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-infant interaction, maternal emotional well-being, social support, control, and adaptation.

[0405] 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.

[0406] The inventors found that elevated scores on the BPRS item "anxiety" and / or the MADRS item "internal tension" negatively impact maternal functioning (maternal competence in interacting with infant(s) and maternal self-care).

[0407] In particular, the inventors have determined that elevated scores on the BPRS item "Anxiety" negatively impact both aspects of maternal functioning (maternal competence related to interactions with infant(s) and maternal self-care). Elevated scores on the BPRS item "Anxiety" impair emotional well-being, social support, and control.

[0408] Conversely, improvement on this BPRS item would translate to improved emotional well-being, social support, and / or control in maternal functioning, particularly in the BIMF domain of functioning.

[0409] Furthermore, the inventors have determined that elevated scores on the MADRS item "internal strain" adversely affect both aspects of maternal functioning (maternal competence related to interactions with infant(s) and maternal self-care). Elevated scores on the MADRS item "internal strain" also impair mother-infant interaction as assessed by the BIMF, and maternal psychological well-being.

[0410] Conversely, improvement on this MADRS item would translate to improvements in maternal functioning, particularly in the BIMF domain of functioning, mother-infant interaction, and / or maternal psychological well-being.

[0411] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve improvement in anxiety.

[0412] We further conclude that the reduction or elimination of anxiety by treating patients with PPD leads to improved maternal functioning, as reflected not only by a reduction in the MADRS total score but also by an increase in the BIMF score.

[0413] The BIMF total score improves by 10% or more, preferably 20% or more.

[0414] Improved maternal function in patients with PPD is reflected by at least an improvement in 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.

[0415] 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, and 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.

[0416] Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed when depression is present most of the time for most days for at least two years. Any symptom-free intervals last less than two months.

[0417] For 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.

[0418] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0419] Patients suffering from persistent depressive disorder may also exhibit symptoms of anxiety, although they have not been diagnosed with an anxiety disorder (subthreshold anxiety).

[0420] As used herein, the term "subthreshold anxiety" specifically means that the patient has a Hamilton Anxiety Rating Scale (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.

[0421] A patient may also be diagnosed with persistent depressive disorder and further diagnosed with an anxiety disorder, i.e., may be considered to have comorbid disorders and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0422] Anxiety symptoms in patients with persistent depressive disorder, such as those with the disorder and subthreshold anxiety disorder, or those with comorbid disorder and anxiety disorder, are associated with greater severity of depression and increased incidence of suicidal ideation.

[0423] Anxiety in patients with persistent depressive disorder may 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."

[0424] Suicidal ideation may be assessed using the "suicidal thoughts" item on the MADRS or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0425] In patients with persistent depressive disorder, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes related to processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal. Functional connectivity impairments are observed within and / or between regions of the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0426] Anxiety is also associated with abnormal connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which may be normalized by treatment according to the present invention.

[0427] Treatment of patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and who have anxiety symptoms, such as patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the disorder.

[0428] Reduction or elimination of anxiety in patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, is observed at about 2 hours, 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.

[0429] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and 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.

[0430] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 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.

[0431] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a decrease 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.

[0432] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and the disorder, a reduction or elimination of anxiety, 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 at about 2 hours, 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.

[0433] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0434] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0435] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and the disorder, 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, 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, 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.

[0436] In patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder, e.g., patients suffering from the disorder and subthreshold anxiety disorder, or patients with a comorbid disorder and anxiety disorder, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0437] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and an anxiety disorder, the reduction or elimination of anxiety, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0438] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "mental anxiety" and / or "somatic anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0439] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0440] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, is observed at about 2 hours, 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.

[0441] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid anxiety and the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "internal tension" item of the MADRS, 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0442] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0443] In patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with a comorbid disorder and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0444] A clinical response in patients with persistent depressive disorder and subthreshold anxiety disorder 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0445] A clinical response in patients with persistent depressive disorder and subthreshold anxiety disorder, 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 pretreatment scores, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0446] The clinical response in patients with persistent depressive disorder 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.

[0447] A clinical response in patients with comorbid persistent depressive disorder and anxiety disorder 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0448] The clinical response in patients with comorbid persistent depressive disorder and 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 pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients with comorbid persistent depressive disorder and 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.

[0449] Remission in patients suffering from persistent depressive disorder, including a treatment-resistant form of the disorder, and subthreshold anxiety, or patients with comorbid anxiety and a disorder, including a treatment-resistant form, is reflected by a HAM-A score of 7 or less and a HAM-D score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0450] In patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a disorder, including treatment-resistant forms, remission, 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 after 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 persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0451] Treatment of patients with persistent depressive disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or patients with comorbid disorders, including treatment-resistant forms, and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0452] In patients suffering from persistent depressive disorder, including a treatment-resistant form of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a disorder, including a treatment-resistant form, a reduction or elimination of suicidal ideation, as reflected by a decrease in the score on the "Suicidal Thoughts" item of the MADRS, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] In patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or in patients with comorbid anxiety and a disorder, including treatment-resistant forms, the reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] Seasonal affective disorder is a mood disorder with a seasonal pattern; symptoms often begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

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

[0456] Patients suffering from seasonal affective disorder may also exhibit symptoms of anxiety, although they have not been diagnosed with an anxiety disorder (subthreshold anxiety).

[0457] As used herein, the term "subthreshold anxiety" specifically means that the patient has a Hamilton Anxiety Rating Scale (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.

[0458] A patient may also be diagnosed with seasonal affective disorder and further diagnosed with an anxiety disorder, i.e., may be considered to have comorbid disorders and anxiety. Such a patient may have a HAM-A score of at least 18 and / or a BAI score of at least 16.

[0459] Anxiety symptoms in patients with seasonal affective disorder, such as those with the disorder and subthreshold anxiety, or those with comorbid disorders and anxiety, are associated with more severe depression and increased incidence of suicidal ideation.

[0460] Anxiety in patients suffering from seasonal affective disorder may 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."

[0461] Suicidal ideation may be assessed using the "suicidal thoughts" item on the MADRS or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0462] Resting-state activity involved in sensorimotor, attention, and visual processing is altered in patients with seasonal affective disorder compared to healthy controls.

[0463] Anxiety is also associated with abnormal connectivity within and / or between resting-state networks, such as the default mode network, the salience network, and the sensorimotor network, which abnormal connectivity can be normalized by treatment in accordance with the present invention.

[0464] Treating patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have comorbid disorders and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and leads to improvement of the disorder.

[0465] Reduction or elimination of anxiety in patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, is observed at about 2 hours, 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.

[0466] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and who have anxiety symptoms, e.g., patients who have the disorder and subthreshold anxiety, or patients who have a comorbid disorder and 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.

[0467] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 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.

[0468] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or resolution of anxiety, as reflected by a decrease in HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or resolution 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.

[0469] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, 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 at about 2 hours, 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.

[0470] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0471] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0472] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, 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, 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, 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.

[0473] In patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, e.g., patients suffering from the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0474] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0475] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0476] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0477] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "inner tension" item of the MADRS, is observed at about 2 hours, 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.

[0478] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "internal tension" item of the MADRS, 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0479] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0480] In patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and with anxiety symptoms, e.g., patients with the disorder and subthreshold anxiety, or patients with comorbid disorders and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0481] A clinical response in patients with seasonal affective disorder and subthreshold anxiety disorder 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0482] A clinical response in patients with seasonal affective disorder and subthreshold anxiety disorder, 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.

[0483] The clinical response in patients with seasonal affective disorder and subthreshold anxiety disorder, 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.

[0484] A 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, compared to the respective scores before treatment, at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] The clinical response in 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 pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in 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.

[0486] Remission in patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or patients with comorbid disorders, including treatment-resistant forms, 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] In patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or in patients with comorbid disorders, including treatment-resistant forms of the disorder, and anxiety, remission, 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 after 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 persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] Treatment of patients with seasonal affective disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety, or patients with comorbid disorders, including treatment-resistant forms, and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0489] In patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, and subthreshold anxiety disorder, or in patients with comorbid disorders, including treatment-resistant forms of the disorder, and anxiety disorder, a reduction or resolution of suicidal ideation, as reflected by a decrease in the score on the "Suicidal Thoughts" item of the MADRS, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 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 forms of the disorder, and subthreshold anxiety disorder, or in patients with comorbid disorders, including treatment-resistant forms of the disorder, and anxiety disorder, reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, preferably persists for at least 6 days, particularly at 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] 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 relapsing, chronic illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0492] 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.

[0493] Patients suffering from BD, including bipolar I disorder and bipolar II disorder, may suffer from treatment-resistant forms of the disorder.

[0494] Patients with BD, whether diagnosed with bipolar II disorder or bipolar I disorder, are particularly susceptible to a current major depressive episode.

[0495] The severity of the current major depressive episode may be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), with the patient's total score being 19 or greater, such as 24 or greater, especially 37 or greater.

[0496] 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.

[0497] Anxiety symptoms are common in BD, and the comorbid diagnosis of any anxiety disorder is higher than major depressive disorder in patients with BD.

[0498] Anxiety is also a commonly reported feature of certain manic episodes, sometimes later referred to as "mixed symptoms."

[0499] Patients with BD may also exhibit symptoms of anxiety, although they have not been diagnosed with an anxiety disorder (subthreshold anxiety).

[0500] As used herein, the term "subthreshold anxiety" specifically means that the patient has a Hamilton Anxiety Rating Scale (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.

[0501] A patient may also be diagnosed with BD and an anxiety disorder, i.e., may 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.

[0502] The presence of comorbid anxiety symptoms is important to identify, as comorbid anxiety disorders increase the risk of suicide in patients with bipolar disorder.

[0503] Anxiety in patients with BD may 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 (global), 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."

[0504] Suicidal ideation may be assessed using the MADRS item "suicidal thoughts," the BDRS item "suicidal ideation," or using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0505] Patients with bipolar disorder exhibit characteristic abnormal intrinsic organization and resting-state network interconnectivity. Resting-state functional magnetic resonance imaging studies have demonstrated altered functional connectivity in specific regions within and / or between the default mode network, salience network, and central executive network compared to healthy controls.

[0506] Anxiety is also associated with abnormal connectivity within and / or between resting-state networks, such as the default mode network and the salience network, which may be normalized by treatment according to the present invention.

[0507] Treating patients with BD, including treatment-resistant forms of BD, who have 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 in BD.

[0508] Reduction or elimination of anxiety in patients suffering from BD, including treatment-resistant forms of BD, e.g., patients suffering from BD and subthreshold anxiety, or patients with comorbid BD and anxiety, is observed at about 2 hours, 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.

[0509] In patients with BD, including treatment-resistant forms of BD, who also have 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 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.

[0510] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in HAM-A score, is observed at about 2 hours, 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.

[0511] In patients with BD, including treatment-resistant forms of 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, as reflected by a decrease in HAM-A score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of 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.

[0512] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, 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 at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0513] In patients with BD, including treatment-resistant forms of 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (the 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.

[0514] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0515] In patients with BD, including treatment-resistant forms of BD, and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with BD and comorbid anxiety, 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, 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, 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.

[0516] In patients suffering from BD, including treatment-resistant forms of BD, e.g., patients suffering from BD and subthreshold anxiety, or patients with BD and comorbid anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the Anxiety / Somatization factor of the Hamilton Rating Scale for Depression (HAM-D), is observed at about 2 hours, 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.

[0517] In patients with BD, including treatment-resistant forms of 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, as reflected by a decrease in the anxiety / somatization factor on the HAM-D, 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, as reflected by a decrease 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.

[0518] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with BD and comorbid anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, is observed at about 2 hours, 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.

[0519] In patients with BD, including treatment-resistant forms of BD, and anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with BD and comorbid anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of the HAM-D, 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, as reflected by a decrease in the score on the "Mental Anxiety" and / or "Somatic Anxiety" items of 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.

[0520] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "internal tension" item of the MADRS, is observed at about 2 hours, 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.

[0521] In patients with BD, including treatment-resistant forms of 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, 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, as reflected by a decrease in the score on the "internal tension" item of the MADRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0522] In patients with BD, including treatment-resistant forms of BD, who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BDRS, is observed at about 2 hours, 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.

[0523] In patients with BD, including treatment-resistant forms of BD, who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BDRS, 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, as reflected by a decrease in the score on the "Anxiety" item of the BDRS, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0524] In patients with BD, including treatment-resistant forms of BD, and who have anxiety symptoms, e.g., patients with BD and subthreshold anxiety, or patients with comorbid BD and anxiety, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0525] In patients with BD, including treatment-resistant forms of 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, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0526] A clinical response in patients with 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0527] A clinical response in patients with BD 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.

[0528] The clinical response in patients with BD 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.

[0529] A 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, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0530] The clinical response in 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 pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in 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.

[0531] Remission in patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or patients with comorbid BD, including treatment-resistant forms of BD 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0532] In patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or patients with comorbid BD, including treatment-resistant forms of BD and anxiety, remission, 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 after 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 persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0533] Treating patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or patients with comorbid BD, including treatment-resistant forms of BD and anxiety, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0534] In patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or in patients with comorbid BD, including treatment-resistant forms of BD and anxiety, a reduction or resolution of suicidal ideation, as reflected by a decrease in the score on the "Suicidal Thoughts" item on the MADRS, is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] In patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or in patients with comorbid BD, including treatment-resistant forms of BD and anxiety, reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the "Suicidal Thoughts" item of the MADRS, preferably persists for at least 6 days, particularly at 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] In patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or in patients with comorbid BD, including treatment-resistant forms of BD, and anxiety, a reduction or resolution of suicidal ideation, as reflected by a decrease in the score on the BDRS item "Suicidal Ideation," is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] In patients with BD, including treatment-resistant forms of BD, and subthreshold anxiety, or patients with comorbid BD, including treatment-resistant forms of BD, and anxiety, reduction or resolution of suicidal ideation, as reflected by a reduction in the score on the BDRS item "Suicidal Ideation," occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or resolution 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.

[0538] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include feelings of tension, panic, and fear, as well as sweating and rapid heartbeat. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system associated with preparation for an anticipated event or situation that is perceived as threatening.

[0539] Patients suffering from an anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0540] The severity of anxiety disorders can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (the 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).

[0541] Anxiety disorders are also associated with suicidal thoughts.

[0542] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0543] Anxiety disorders are examined by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). The other networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting balance within and / or between these networks (e.g., SMN and SN) relative to the DMN may be abnormal in different anxiety disorders.

[0544] Treating patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0545] The reduction or elimination of anxiety in a patient suffering from an anxiety disorder is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] The reduction or elimination of 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.

[0547] A clinical response in patients suffering from an anxiety disorder, including treatment-resistant forms of the disorder, is reflected by at least a 50% decrease in the HAM-A score compared to pre-treatment, about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0548] In patients suffering from an 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from an 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 preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0549] Remission of anxiety in patients suffering from such anxiety disorders, including treatment-resistant forms of the disorders, is reflected by a HAM-A score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0550] Remission of anxiety in patients suffering from such anxiety disorders, including treatment-resistant forms of the disorder, as reflected by a HAM-A score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety in patients suffering from such anxiety disorders, 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.

[0551] In patients suffering from an anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 at about 2 hours, 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.

[0552] In patients suffering from anxiety disorders, including treatment-resistant forms of disorders, 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), 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, 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.

[0553] In patients suffering from an anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0554] In patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, 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, 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, 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.

[0555] In patients suffering from an anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0556] In patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, the reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, 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, 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.

[0557] Treatment of patients suffering from anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0558] In patients suffering from an anxiety disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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] In patients suffering from anxiety disorders, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0560] The above applies to anxiety disorders generally, including the specific conditions detailed below, as well as anxiety disorders due to medical conditions, which occur when a medical condition causes extreme fear, anxiety, or panic; other specific anxiety disorders, which may be diagnosed when a patient meets most but not all of the criteria for an anxiety disorder; and unspecified anxiety disorder, which is often diagnosed when a patient is experiencing anxiety or panic but there is insufficient information to fully diagnose another anxiety disorder.

[0561] Separation anxiety disorder is characterized by excessive anxiety about separation from home and / or from people to whom the sufferer has strong attachments.

[0562] Separation situations can be very distressing for patients, and the separation can make it difficult for them 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.

[0563] Patients suffering from separation anxiety disorder may suffer from a treatment-resistant form of the disorder.

[0564] The severity of separation anxiety 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 (items 1-6 and 14 combined), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0565] Separation anxiety disorder is also associated with suicidal ideation.

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

[0567] 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 these networks (e.g., SMN and SN) relative to the DMN may be abnormal in different anxiety disorders.

[0568] 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.

[0569] The reduction or elimination of anxiety in a patient suffering from separation anxiety disorder is observed at about 2 hours, 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 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.

[0571] 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 compared to pre-treatment, about 2 hours, 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.

[0572] A clinical response in patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, reflected by at least a 50% reduction in the HAM-A score compared to the respective score before treatment, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response in patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, 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 such patients suffering from 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0574] Remission 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission 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.

[0575] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0576] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, 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), 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, 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.

[0577] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours, 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] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, 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, 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, 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.

[0579] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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 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.

[0582] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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] In patients suffering from separation anxiety disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0584] Agoraphobia is the fear of situations or places that can cause panic, feelings of blockage, helplessness, or isolation.

[0585] People with agoraphobia may find it difficult to leave the house. Just the thought of leaving the house can cause so much anxiety that they want to avoid it. Fears of crowds, travel, elevators, movie theaters, shopping malls, etc. can cause significant problems.

[0586] Patients with agoraphobia may also have recurrent panic attacks.

[0587] Patients suffering from agoraphobia may have a treatment-resistant form of the disorder.

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

[0589] Agoraphobia has also been associated with suicidal thoughts.

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

[0591] Functional magnetic resonance imaging in individuals with agoraphobia reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0592] 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.

[0593] The reduction or elimination of anxiety in a patient suffering from agoraphobia is observed at about 2 hours, 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 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.

[0595] A clinical response in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, is reflected by at least a 50% decrease in the HAM-A score compared to pre-treatment, about 2 hours, 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.

[0596] A clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective pre-treatment score in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response reflected by at least a 50% reduction in the HAM-A score in patients suffering from agoraphobia, including treatment-resistant forms of the disorder, persists preferably for at least 6 days, particularly at 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 patients 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0598] Remission 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission 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.

[0599] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0600] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the HAM-A Mental 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] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours, 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] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, 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, 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, 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] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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 agoraphobia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0606] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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] In patients suffering from agoraphobia, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0608] Generalized anxiety disorder (GAD) is characterized by persistent, excessive, and uncontrollable worry about a wide range of situations and problems. People with GAD may anticipate difficulties and worry excessively about money, health, family, work, or other problems.

[0609] GAD is diagnosed when patients experience persistent worry about everyday challenges that is out of proportion to the perceived threat. Patients with GAD typically experience excessive fear that can last for months or even years.

[0610] GAD interferes with social, occupational, or other important areas of functioning.

[0611] Patients with GAD may have a treatment-resistant form of the disorder.

[0612] 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 (the 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] GAD is also associated with suicidal ideation.

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

[0615] Patients with GAD also show altered functional connectivity, particularly within the default mode network.

[0616] 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.

[0617] The reduction or elimination of anxiety in a patient with GAD is observed at about 2 hours, 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.

[0618] 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.

[0619] A clinical response in patients with GAD, including treatment-resistant forms of the disorder, is reflected by at least a 50% decrease in the HAM-A score compared to pre-treatment, about 2 hours, 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.

[0620] 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 after 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.

[0621] 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, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] Remission of anxiety in patients suffering from such GAD, including treatment-resistant forms of the disorder, as reflected by a HAM-A score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety in patients suffering from such GAD, 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] In patients with GAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0624] In patients suffering from GAD, including treatment-resistant forms of the disorder, 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), 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, 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.

[0625] In patients suffering from GAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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] In patients with GAD, including treatment-resistant forms of the disorder, 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, 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, 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.

[0627] In patients suffering from GAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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] In patients with GAD, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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 with GAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0630] In patients suffering from GAD, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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] In patients with GAD, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation 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.

[0632] Social anxiety disorder (SAD), also known as social phobia, is one of the most common types of anxiety.

[0633] SAD is characterized by intense anxiety or fear of being judged, negatively evaluated, or rejected in social or performance situations. This often leads to avoidance of social situations and can cause impairment in school, work, or relationships.

[0634] Patients with SAD may have a treatment-resistant form of the disorder.

[0635] 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 (the 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).

[0636] SAD is also associated with suicidal thoughts.

[0637] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0638] In patients with SAD, altered functional connectivity is observed within and / or between resting-state networks, such as the default mode network and the salience network.

[0639] 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.

[0640] The reduction or elimination of anxiety in a patient suffering from SAD is observed at about 2 hours, 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.

[0641] The reduction or elimination of anxiety in a patient suffering from 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.

[0642] 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 compared to pre-treatment, about 2 hours, 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.

[0643] 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 after 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.

[0644] Remission of anxiety in such patients suffering from SAD, including treatment-resistant forms of the disorder, is reflected by a HAM-A score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] Remission 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission 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.

[0646] In patients suffering from SAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0647] In patients suffering from SAD, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the HAM-A Mental 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.

[0648] In patients suffering from SAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0649] In patients suffering from SAD, including treatment-resistant forms of the disorder, 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, 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, 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.

[0650] In patients suffering from SAD, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0651] In patients suffering from SAD, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, 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, 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.

[0652] Treating patients with SAD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0653] In patients suffering from SAD, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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.

[0654] In patients with SAD, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0655] 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.

[0656] Panic attacks are characterized by many somatic anxiety symptoms, including sweating, trembling, shaking, headache, palpitations, shortness of breath, chest pain, abdominal pain, and nausea.

[0657] Additionally, the disorder can often be characterized by anxiety about future panic attacks, and patients may become preoccupied with fear of recurrent attacks.

[0658] Patients suffering from panic disorder may suffer from a treatment-resistant form of the disorder.

[0659] 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 (the 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] Panic disorder is also associated with suicidal thoughts.

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

[0662] Patients with panic disorder exhibit altered functional connectivity within and / or between the default mode network and the sensorimotor network.

[0663] 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.

[0664] The reduction or elimination of anxiety in a patient suffering from a panic disorder is observed at about 2 hours, 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 suffering from a 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.

[0666] 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 compared to pre-treatment, about 2 hours, 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.

[0667] 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 after 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.

[0668] Remission of anxiety in patients suffering from such panic disorders, including treatment-resistant forms of the disorder, is reflected by a HAM-A score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] Remission of anxiety in patients suffering from such panic disorder, including treatment-resistant forms of the disorder, as reflected by a HAM-A score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety in patients suffering from such panic 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.

[0670] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 at about 2 hours, 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] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), 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, as reflected by a decrease 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] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours, 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] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, 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, 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, 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.

[0674] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, 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, 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 panic disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0677] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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] In patients suffering from panic disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0679] A phobia is an anxiety disorder defined by a persistent and excessive fear of an object or situation. Patients suffering from a phobia experience extreme anxiety when they anticipate or are exposed to the phobic stimulus. There are animal-type (spiders, snakes, dogs) phobias, environmental-type (tornadoes, heights, water, fire) phobias, blood-injection-type (needles, medical procedures) phobias, situational-type (flying in an airplane, enclosed spaces) phobias, and other types of phobias (phobias that do not fit into any of the above categories).

[0680] Phobias usually result in a rapid onset of fear, usually present for more than six months. Patients make significant efforts to avoid the phobic stimulus. The fear and avoidance cause significant distress and / or impairment in occupational, academic, or social functioning.

[0681] Patients suffering from phobias may suffer from treatment-resistant forms of the disorder.

[0682] The severity of phobias 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).

[0683] Phobias are also associated with suicidal ideation.

[0684] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0685] In individuals with specific phobias, the amygdala, anterior cingulate cortex (ACC), and insular cortex all appear to be hyperresponsive to phobia-related stimuli. For example, functional neuroimaging studies have revealed that the dorsal portion of the anterior cingulate cortex (dACC), which is part of the salience network, is hyperresponsive to phobia-related stimuli or the anticipation of such stimuli.

[0686] Treating patients suffering from phobias, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0687] A reduction or elimination of anxiety in a patient suffering from a phobia is observed at about 2 hours, 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.

[0688] The reduction or elimination of anxiety in a patient suffering from a phobia occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] A clinical response in patients suffering from phobia, including treatment-resistant forms of the disorder, is reflected by at least a 50% decrease in the HAM-A score compared to pre-treatment, about 2 hours, 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.

[0690] In patients suffering from a phobia, 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In patients suffering from a phobia, 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.

[0691] Remission of anxiety in patients suffering from such phobias, including treatment-resistant forms of the disorder, is reflected by a HAM-A score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0692] Remission of anxiety in patients suffering from such phobias, including treatment-resistant forms of the disorder, as reflected by a HAM-A score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety in patients suffering from such phobias, 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.

[0693] In patients suffering from a phobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0694] In patients suffering from phobias, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the HAM-A Mental Anxiety subscale (sum of items 1-6 and 14), 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, as reflected by a decrease in the score on the HAM-A Mental 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.

[0695] In patients suffering from a phobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the anxious mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0696] In patients suffering from phobias, including treatment-resistant forms of the disorder, 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, 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, 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.

[0697] In patients suffering from a phobia, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0698] In patients suffering from phobias, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, 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, as reflected by a decrease 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.

[0699] Treating patients suffering from phobia, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates suicidal ideation.

[0700] In patients suffering from a phobia, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 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.

[0701] In patients suffering from phobia, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0702] Substance / drug-induced anxiety disorder is an anxiety disorder in which anxiety or panic occurs after use of alcohol, drugs of abuse, or other substances, or after exposure to toxins. Substance / drug-induced anxiety disorder causes prominent symptoms of panic or anxiety and can occur during the intoxication or withdrawal phases of substance or drug use.

[0703] The disturbance causes clinically significant difficulty or impairment in social, occupational, or other important areas of functioning.

[0704] While taking a substance or medication, or shortly after, an individual suffering from substance / drug-induced anxiety disorder may feel nervous or anxious, experience symptoms of negative thinking, have difficulty concentrating or remembering, fear of losing control or becoming psychotic or dying, lose weight due to gastrointestinal problems, have chills, hot flashes, sweating, trembling, numbness, or palpitations, difficulty breathing, difficulty swallowing, or chest pain.

[0705] The severity of substance / drug-induced anxiety disorders can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (items 1-6 and 14 combined), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0706] Substance / drug-induced anxiety disorders are further associated with suicidal ideation.

[0707] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0708] Functional magnetic resonance imaging in individuals suffering from substance / drug-induced anxiety disorders reveals altered functional connectivity within and / or between resting-state networks involved in anxiety.

[0709] Treatment of patients suffering from substance / drug-induced anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0710] A reduction or elimination of anxiety in a patient suffering from a substance / drug-induced anxiety disorder is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0711] The reduction or elimination of anxiety in a patient suffering from a substance / drug-induced anxiety disorder occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] A clinical response in patients suffering from a substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, is reflected by at least a 50% decrease in the HAM-A score compared to pre-treatment, about 2 hours, 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.

[0713] A clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective pre-treatment score in patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response reflected by at least a 50% reduction in the HAM-A score in patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0714] Remission of anxiety in patients suffering from such substance / drug-induced anxiety disorders, including treatment-resistant forms of the disorders, is reflected by a HAM-A score of 7 or less at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or about 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0715] Remission of anxiety in patients suffering from such substance / drug-induced anxiety disorders, including treatment-resistant forms of the disorders, as reflected by a HAM-A score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety in patients suffering from such substance / drug-induced anxiety disorders, including treatment-resistant forms of the 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.

[0716] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, 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 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.

[0717] In patients suffering from substance / drug-induced anxiety disorders, including treatment-resistant forms of the disorders, 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), 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, 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.

[0718] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Anxious Mood item (item 1) of the HAM-A, is observed at about 2 hours, 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.

[0719] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, 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, 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, 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.

[0720] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, a reduction or elimination of anxiety, as reflected by a decrease in the score on the "Anxiety" item of the BPRS, is observed at about 2 hours, 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.

[0721] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, the reduction or elimination of anxiety, as reflected by a reduction in the score on the "Anxiety" item of the BPRS, 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, 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.

[0722] Treatment of patients suffering from substance / drug-induced anxiety disorders, including treatment-resistant forms of the disorders, with 5-MeO-DMT or its pharmaceutically acceptable salts reduces or eliminates suicidal ideation.

[0723] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0724] In patients suffering from substance / drug-induced anxiety disorder, including treatment-resistant forms of the disorder, reduction or elimination of suicidal ideation occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Reduction or elimination of 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.

[0725] somatic symptom disorder Somatic symptom disorder is a mental disorder diagnosed when a person is markedly focused on physical symptoms, such as pain, weakness, or shortness of breath, to the point of causing significant distress and / or impairment of functioning and / or interference with daily life. Illness-related emotions and behaviors are excessive or disproportionate.

[0726] Health-related quality of life is often impaired, both physically and mentally. In severe somatic symptom disorders, the impairment is significant and, if persistent, can lead to disability.

[0727] Somatic symptom disorder can be assessed using the DSM-5 Level 2 - Somatic Symptoms - Adult scale. This scale includes 15 somatic symptoms. Respondents are asked to rate the severity of their somatic symptoms over the past seven days. Total scores can range from 0 to 30, with higher scores indicating greater somatic symptom severity. Cutoff scores of 5, 10, and 15 indicate low, moderate, and high somatic symptom severity, respectively.

[0728] Additionally, anxiety in individuals with somatic symptom 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 (the 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).

[0729] Patients suffering from somatic symptom disorder and anxiety symptoms also tend to suffer from suicidal ideation.

[0730] Suicidal ideation may be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0731] Functional brain connectivity analyses reveal alterations within and / or between resting-state networks in patients with somatic symptom disorder compared to healthy controls. Alterations are identified within and / or between the default mode network (DMN), salience network, dorsal attention network (DAN), and sensorimotor network. Somatic symptom disorder may be associated with altered sensory discrimination processing of somatic symptoms, which is influenced by emotional processing.

[0732] Anxiety is also associated with abnormal connectivity within and / or between networks, which may be normalized by treatment according to the present invention.

[0733] Treatment of patients with somatic symptom disorder, including treatment-resistant forms, and anxiety, such as patients with somatic symptom disorder and subthreshold anxiety disorder, or patients with comorbid somatic symptom disorder and anxiety disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety and results in improvement of the somatic symptom disorder.

[0734] In patients with somatic symptom disorder, including treatment-resistant forms, and anxiety, e.g., patients with somatic symptom disorder and subthreshol...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof for use in treating a patient suffering from anxiety, wherein said 5-MeO-DMT is administered via an intravenous, intramuscular, or subcutaneous route.

2. 2. The method of claim 1, wherein the anxiety disorder suffered by the patient is subthreshold anxiety.

3. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1 or claim 2, wherein the patient has a comorbid disorder further diagnosed as anxiety.

4. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein the patient also suffers from a psychiatric or neurological disorder.

5. 5. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 4, wherein the patient also suffering from said psychiatric or neurological disorder suffers from a treatment-resistant form of said disorder.

6. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from a disorder characterized by depressive episodes.

7. 7. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 6, wherein the patient also suffering from a disorder characterized by depressive episodes suffers from a treatment-resistant form of the disorder.

8. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from major depressive disorder (MDD).

9. 9. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 8, wherein the patient also suffering from MDD suffers from a treatment-resistant form of the disorder.

10. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from postpartum depression (PPD).

11. 11. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 10, wherein the patient also suffering from PPD suffers from a treatment-resistant form of the disorder.

12. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 10 or 11, wherein the patient further suffers from maternal dysfunction.

13. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 12, wherein the patient has a Birkin Index of Maternal Function (BIMF) score of 80 or less, such as 65 or less.

14. 14. The method of claim 12, wherein the treatment improves maternal function.

15. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 14, wherein the improvement in maternal function is reflected by an improvement in the BIMF total score of 10% or more, preferably 20% or more.

16. 16. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 14 or 15, wherein the improved maternal function is reflected by at least an improvement in BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

17. 16. The method of claim 14 or 15, wherein the improvement in maternal function as reflected by at least an improvement in the BIMF sum score occurs within about 6 days after the last administration of the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the improvement in maternal function as reflected by at least an improvement in the BIMF sum score persists until at least 14 days after the last administration of the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and more preferably, until at least 28 days after the last administration of the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from persistent depressive disorder.

19. 19. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 18, wherein the patient also suffering from persistent depressive disorder suffers from a treatment-resistant form of the disorder.

20. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from seasonal affective disorder.

21. 21. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 20, wherein the patient also suffering from seasonal affective disorder suffers from a treatment-resistant form of the disorder.

22. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from bipolar disorder.

23. 23. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 22, wherein the patient is also suffering from bipolar II disorder.

24. 23. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 22, wherein the patient is also suffering from bipolar I disorder.

25. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 22 to 24, wherein the patient is currently suffering from a major depressive episode.

26. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 22 to 25, wherein the patient who is also suffering from bipolar disorder is suffering from a treatment-resistant form of the disorder.

27. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from an anxiety disorder.

28. 28. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 27, wherein the patient suffering from an anxiety disorder is suffering from a treatment-resistant form of the disorder.

29. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from separation anxiety disorder.

30. 30. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 29, wherein the patient suffering from separation anxiety disorder is suffering from a treatment-resistant form of the disorder.

31. 2. The method of claim 1, wherein the patient is suffering from agoraphobia.

32. 32. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 31, wherein the patient suffering from agoraphobia is suffering from a treatment-resistant form of the disorder.

33. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from generalized anxiety disorder (GAD).

34. 34. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 33, wherein the patient suffering from GAD is suffering from a treatment-resistant form of the disorder.

35. 2. The method of claim 1, wherein the patient is suffering from social anxiety disorder (SAD).

36. 36. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 35, wherein the patient suffering from SAD suffers from a treatment-resistant form of the disorder.

37. 2. The method of claim 1, wherein the patient is suffering from a panic disorder.

38. 38. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 37, wherein the patient suffering from panic disorder is suffering from a treatment-resistant form of the disorder.

39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from a phobia.

40. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 39, wherein the patient suffering from the phobia suffers from a treatment-resistant form of the disorder.

41. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 1, wherein the patient is suffering from a substance / drug-induced anxiety disorder.

42. 42. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 41, wherein the patient suffering from substance / drug-induced anxiety disorder is suffering from a treatment-resistant form of the disorder.

43. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from a somatic symptom disorder.

44. 44. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 43, wherein the patient also suffering from the somatic symptom disorder suffers from a treatment-resistant form of the disorder.

45. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from an obsessive-compulsive or related disorder.

46. 46. ​​The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 45, wherein the obsessive-compulsive or related disorder is obsessive-compulsive disorder (OCD).

47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 45 or 46, wherein the patient is suffering from a treatment-resistant form of the disorder.

48. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from body dysmorphic disorder (BDD).

49. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 48, wherein the patient also suffering from BDD suffers from a treatment-resistant form of the disorder.

50. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from post-traumatic stress disorder (PTSD).

51. 51. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 50, wherein the patient who is also suffering from PTSD is suffering from a treatment-resistant form of the disorder.

52. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from a pain disorder.

53. 53. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 52, wherein the patient is also suffering from chronic pain.

54. 54. ...-MeO-DMT, or a pharma- ceutically acceptable salt thereof, for use according to claim 52 or 53, wherein the patient is suffering from a treatment-resistant form of the disorder.

55. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from fibromyalgia.

56. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from migraine headaches.

57. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from psychiatric and behavioral disorders resulting from the use of psychoactive substances.

58. 58. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 57, wherein the psychiatric and behavioral disorder resulting from the use of psychoactive substances from which the patient is suffering is a substance use disorder (SUD).

59. 59. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 57 or 58, wherein the patient is suffering from a treatment-resistant form of the disorder.

60. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from a psychotic disorder.

61. 61. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 60, wherein the patient who is also suffering from a psychotic disorder is suffering from a treatment-resistant form of the disorder.

62. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from schizophrenia.

63. 63. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 62, wherein the patient also suffering from schizophrenia suffers from a treatment-resistant form of the disorder.

64. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from Parkinson's disease.

65. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from dementia.

66. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from Alzheimer's dementia.

67. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from Parkinson's disease dementia.

68. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from dementia with Lewy bodies.

69. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from vascular dementia.

70. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from frontotemporal dementia.

71. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from an eating disorder.

72. 72. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 71, wherein the patient also suffering from an eating disorder suffers from a treatment-resistant form of the disorder.

73. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from Attention Deficit Hyperactivity Disorder (ADHD).

74. 74. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 73, wherein the patient who is also afflicted with ADHD is afflicted with a treatment-resistant form of the disorder.

75. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from a personality disorder.

76. 76. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 75, wherein the personality disorder from which the patient suffers is schizotypal personality disorder.

77. 77. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 75 or 76, wherein the patient is suffering from a treatment-resistant form of the disorder.

78. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from borderline personality disorder (BPD).

79. 79. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 78, wherein the patient also suffering from BPD suffers from a treatment-resistant form of the disorder.

80. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient is also suffering from chronic fatigue syndrome.

81. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from an autism spectrum disorder.

82. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient suffers from a traumatic brain injury and also suffers from anxiety.

83. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient suffers from HIV infection and also suffers from anxiety.

84. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient suffers from a pathological condition of the sequelae of COVID and also suffers from anxiety.

85. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein said treatment reduces or eliminates anxiety.

86. 86. The method of claim 85, wherein the reduction or elimination of anxiety is observed at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

87. 86. The method of claim 85, wherein the reduction or elimination of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the reduction or elimination of anxiety persists for at least 6 days, in particular at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

88. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 4 to 26 and 43 to 87, wherein the treatment leads to an improvement of the diagnosed disorder in a patient who also suffers from anxiety.

89. 89. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 88, wherein improvement of the diagnosed disorder as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores in patients who also suffer from anxiety is observed at about 2 hours, 1 day, e.g., at about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

90. 89. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 88, wherein the improvement of the diagnosed disorder as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score in a patient who is also suffering from anxiety occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and wherein the improvement of the diagnosed disorder as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score in a patient who is also suffering from anxiety persists for at least 6 days, in particular at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

91. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 3, wherein the patient also suffers from a sleep disorder.

92. 92. The 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 91, wherein the sleep disorder is insomnia.

93. 93. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 91 or 92, wherein the patient is suffering from a treatment-resistant form of the disorder.

94. The sleep disorder is affected by anxiety, and may be a mental or nervous system disorder, for example a disorder 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 / drug-induced anxiety disorders; somatic symptom disorder; 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 resulting from the use of psychoactive substances, such as substance use disorders.

94. 5-MeO-DMT or a pharmacologic acceptable salt thereof for use according to any one of claims 91 to 93, wherein the 5-MeO-DMT or a pharmacologic acceptable salt thereof for use according to any one of claims 91 to 93 occurs in a patient who also suffers from a disorder including, but not limited to, a psychotic disorder, e.g., schizophrenia; Parkinson's disease; dementia, e.g., Alzheimer's dementia (AD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, vascular dementia, frontotemporal dementia; an eating disorder; Attention Deficit Hyperactivity Disorder (ADHD); personality disorder, e.g., schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; or a medical health condition leading to an associated mental or neurological pathology, e.g., anxiety due to traumatic brain injury (TBI), HIV infection, or post-COVID pathology.

95. 95. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 94, wherein said treatment results in improvement of anxiety and sleep disorders and further results in improvement of said associated psychiatric or neurological disorder, or a medical condition leading to said associated mental or neurological pathology.

96. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 85 to 95, wherein said treatment results in an improvement in said sleep disorder.

97. 97. The method of claim 96, wherein the improvement in the sleep disorder, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, is observed on the 1st day, e.g., about 24 hours, 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

98. 97. The method of claim 96, wherein the improvement in the sleep disorder as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score occurs within about 24 hours of the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and the improvement in the sleep disorder as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score persists for at least 6 days, in particular at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

99. 97. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 96, wherein the improvement in the sleep disorder, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, is observed 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and preferably persists for at least 14 days, more preferably for at least 28 days.

100. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein the patient is suffering from suicidal ideation and the treatment reduces or eliminates the suicidal ideation.

101. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein the 5-MeO-DMT or a salt thereof is administered in a dose or dosing regimen that causes the patient to experience a hallucinogenic high experience.

102. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

103. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 101, wherein a dosage of about 2 mg, or about 5 mg, or about 8 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

104. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 101, wherein a dosage of about 1 mg, or about 2 mg, or about 3 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

105. 103. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 102, wherein the 5-MeO-DMT or a salt thereof is administered in a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, each subsequent administration using a higher dosage than the previous administration unless the patient experiences a hallucinogenic high experience.

106. 106. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 102 or 105, wherein the 5-MeO-DMT is administered at a dosage of about 1 mg to about 3 mg for a first administration, then increased to a dosage of about 4 mg to about 6 mg for a second administration, unless the patient has already experienced a hallucinatory high experience, and then increased to a dosage of about 7 mg to about 9 mg for a third administration, unless the patient has already experienced a hallucinatory high experience, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

107. 107. The method of claim 106, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

108. 106. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claims 1-102 or 105, wherein the 5-MeO-DMT is administered at a dosage of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has already experienced a hallucinatory high experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a hallucinatory high experience, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

109. 109. The method of claim 108, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered in place of 5-MeO-DMT.

110. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 105 to 109, wherein the interval between two administrations is at least 1 hour and at most 24 hours, for example about 1 to 4 hours, preferably 1 to 2 hours.

111. 111. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 101 to 110, wherein the onset of a hallucinatory peak experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving at least 75 on the Peak Experience Scale (PES) Total Score.

112. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to claim 111, wherein the onset of the hallucinogenic peak experience is identified by achieving a Peak Experience Scale (PES) Total Score of at least 75.

113. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of the preceding claims, wherein the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous injection.

Images